Table of Contents
Overview
Definition and Components
The tumor microenvironment (TME) is defined as a complex ecosystem that surrounds a tumor, comprising not only cancer cells but also various stromal components, including blood vessels, immune cells, fibroblasts, signaling molecules, and the extracellular matrix. This intricate environment plays a crucial role in supporting tumor growth and invasion into healthy tissues, which is often associated with resistance to current treatments and poor patient prognosis.[1.1] The TME is characterized by a diverse array of components that interact with tumor cells, making it essential to understand these interactions for the development of more effective therapeutic strategies.[2.1] Among the critical elements of the TME are immune cells, which can exhibit a dual role: they may either suppress tumor growth or promote it, depending on the specific context.[3.1] Additionally, key processes such as angiogenesis (the formation of new blood vessels), hypoxia (low oxygen levels), and chronic inflammation are significant drivers of tumor growth, metastasis, and treatment resistance.[4.1] The composition of the tumor microenvironment can vary significantly between different tumor types, but it consistently includes immune cells, stromal cells, blood vessels, and the extracellular matrix. This composition underscores the notion that the TME is not merely a passive bystander but an active participant in cancer progression.[5.1] Furthermore, the interplay between various cell types within the TME is critical for understanding the initiation and progression of malignancies, highlighting the importance of this microenvironment in improving molecular diagnostics and therapeutic approaches.[6.1]Role in Cancer Progression
The tumor microenvironment (TME) is pivotal in cancer progression due to its complex interactions with tumor cells and various immune and stromal cell types. These interactions stimulate cancer cell heterogeneity, promote clonal evolution, and increase multidrug resistance, contributing to cancer progression and metastasis.[9.1] Tumor-infiltrating immune cells play a significant role by inducing epigenetic alterations in both stromal and tumor cells, impacting disease outcomes.[12.1] Chronic inflammation within the TME further elevates cancer risk and progression, as these immune cells drive epigenetic changes that affect disease outcomes.[7.1] The intricate relationship between cancer cells and the TME influences cancer progression and therapeutic responses, highlighting the need for a deeper understanding of these interactions to develop effective treatment strategies.[8.1] Recent research underscores the importance of a TME-centric approach in cancer treatment, focusing on innovative strategies such as stromal reprogramming, immune microenvironment modulation, and extracellular matrix-targeting agents to enhance treatment outcomes by addressing the complex dynamics of the TME.[19.1] Moreover, as the tumor grows, reciprocal interactions between tumor cells and associated immune and stromal cells evolve, modulating intrinsic and extrinsic processes that influence tumor behavior.[10.1] This complexity necessitates a shift from a cancer-centric model to a TME-centric approach in cancer research and treatment, emphasizing the need to consider factors within the TME, such as immune cell diversity, metabolic conditions, and the presence of hypoxic or acidic niches.[19.1] Understanding these factors is crucial for developing personalized treatment plans that effectively target the unique characteristics of each tumor's microenvironment.[18.1]In this section:
History
Early Theories and Discoveries
The concept of the tumor microenvironment (TME) has evolved significantly over the past century, beginning with early theories that emphasized the interactions between cancer cells and their surrounding environment. Stephen Paget first proposed the idea that cancer progression is regulated by these interactions over a century ago, laying the groundwork for contemporary research in the field.[51.1] The TME is now understood as a complex ecosystem that includes not only cancer cells but also various non-cancerous cells, such as stromal tissue, immune cells, fibroblasts, and blood vessels, all embedded within an altered extracellular matrix.[53.1] This intricate network facilitates mutual interactions that support tumor growth and invasion into healthy tissues, which are associated with resistance to treatments and poor patient prognosis.[52.1] Historically, the focus of oncology was predominantly tumor-centric, particularly during the latter half of the twentieth century, where the primary emphasis was on identifying therapeutic targets within tumor cells.[54.1] However, since the early 2000s, there has been a paradigm shift towards recognizing the critical role of the TME in cancer progression, patient outcomes, and therapeutic responses.[55.1] This transition has been driven by accumulating evidence that highlights how both cellular and acellular components of the TME can influence tumor initiation, growth, and metastasis, thereby necessitating a more comprehensive understanding of cancer biology.[56.1]Key Contributions to Tumor Microenvironment Research
Understanding the tumor microenvironment (TME) has become increasingly vital in cancer research, influencing the development of personalized medicine strategies. The TME is a complex ecosystem that includes various components such as blood vessels, fibroblasts, immune cells, signaling molecules, exosomes, and the extracellular matrix (ECM).[57.1] This intricate relationship between cancer cells and their surrounding environment significantly impacts tumor progression and therapeutic responses.[60.1] Recent advancements in personalized medicine (PM) have highlighted the importance of considering inter- and intra-tumor variability, which encompasses genetic factors, the immune environment, and individual patient characteristics.[59.1] For instance, colorectal cancer has served as a prominent model for implementing tumor-tailored treatments, demonstrating the potential of personalized approaches in oncology.[59.1] Furthermore, the role of the immune community within the TME has been recognized as crucial in tumorigenesis and tumor evolution, with immune cells communicating with tumor cells through ligand-receptor interactions.[63.1] Bioinformatics tools have played a significant role in enhancing our understanding of cellular interactions within the TME. These tools have facilitated the discovery of previously unknown rare cell types and have allowed for the construction of detailed single-cell atlases of tumors, which are essential for elucidating cellular composition and interactions.[65.1] Such insights have informed therapeutic strategies, particularly in the context of immunotherapy, where the interactions between immune cells and cancer cells can dictate treatment efficacy.[71.1] The dynamic interactions within the TME also extend to cancer-associated fibroblasts and immune cells, which influence each other's behavior and can alter the overall tumor phenotype, thereby impacting therapeutic responses.[68.1] The cross-talk between various cell types in the TME leads to changes in the structural and biological properties of the ECM, promoting tumor proliferation, invasion, and metastasis.[70.1] As research continues to unravel the complexities of the TME, it is clear that these insights are pivotal for developing more effective cancer therapies and improving patient outcomes.In this section:
Recent Advancements
Current Research Trends
Recent research on the tumor microenvironment (TME) has increasingly focused on its complexity and the dynamic interactions between cancer cells and their surrounding environment. The TME is not merely a passive backdrop for tumor growth; it is a heterogeneous collection of various cell types, including immune cells, stromal cells, and components of the extracellular matrix (ECM), which collectively influence cancer progression and therapeutic responses.[98.1] This bidirectional communication allows tumor cells to reprogram the TME to support their own growth while simultaneously affecting the genetic and epigenetic landscape of the tumor cells, contributing to cancer heterogeneity and drug resistance.[100.1] Recent advancements in high-throughput technologies have enhanced our understanding of the factors influencing tumor heterogeneity, revealing that these drivers can originate from both intrinsic tumor characteristics and the TME itself.[123.1] For instance, cancer-associated fibroblasts (CAFs), which are prevalent in the TME of most solid tumors, have been identified as key regulators of cancer progression and response to therapy.[124.1] The molecular heterogeneity of CAFs at the single-cell level has been a significant focus, although the functional roles of many CAF populations remain to be fully defined.[124.1] Moreover, the role of tumor microbiota has emerged as a critical area of study, as these microbial communities can modulate oncogenic signals, alter tumor metabolism, and foster an immunosuppressive environment, thereby influencing cancer pathophysiology.[100.1] The interplay between tumor cells and immune cells within the TME can either suppress tumor formation or promote tumorigenesis, highlighting the complexity of these interactions.[98.1] Research has also explored the implications of tumor cell metabolism on the TME, particularly how oncogene-driven metabolic changes can limit immune responses and create barriers to effective cancer therapies.[99.1] Understanding these intricate relationships is essential for developing novel therapeutic strategies aimed at disrupting the interplay between cancer cells and their microenvironment, ultimately contributing to more effective cancer treatments.[121.1]Therapeutic Strategies Targeting the Tumor Microenvironment
Therapeutic strategies targeting the tumor microenvironment (TME) have gained significant attention due to their potential to enhance cancer treatment efficacy. Recent advancements highlight the importance of understanding the complex interactions within the TME, which includes various non-malignant cells such as immune cells, fibroblasts, and endothelial cells, as well as the extracellular matrix. These interactions play a crucial role in shaping cancer progression and therapy response.[110.1] One promising approach involves the use of nanomedicines that are designed to target specific components of the TME. For instance, nanobodies targeting the tumor microenvironment have been formulated as nanomedicines, which can deliver therapeutic agents directly to cancer cells and immune cells, thereby improving treatment outcomes.[103.1] This strategy leverages the unique characteristics of the TME to enhance the specificity and efficacy of cancer therapies. Moreover, the TME presents both opportunities and challenges for immunotherapy. The dynamic interactions between tumor cells and immune cells can either dampen or enhance immune responses, influencing the overall effectiveness of treatments such as immune checkpoint inhibitors.[108.1] Techniques like single-cell RNA sequencing are being utilized to better understand these interactions, guiding the selection of appropriate immunotherapeutic strategies.[111.1] Targeting the TME also offers a significant therapeutic advantage over directly targeting cancer cells. Non-tumor cells within the TME are generally more genetically stable and less prone to drug resistance, making them more vulnerable to therapeutic interventions.[106.1] For example, cancer-associated fibroblasts (CAFs) can secrete factors that protect tumor cells from immune attacks, thus targeting these fibroblasts may enhance the effectiveness of immune checkpoint blockade therapies.[106.1] Recent studies have emphasized the need for a TME-centric approach in cancer treatment, moving away from traditional cancer-centric models. This shift is supported by accumulating evidence that highlights the role of various TME components, such as hypoxic niches and immune microenvironments, in modulating cancer therapies.[105.1] By focusing on these aspects, researchers aim to develop more effective and personalized treatment strategies that can be tailored to the specific characteristics of a patient's tumor.[107.1]Tumor Microenvironment Composition
Cellular Components
The tumor microenvironment (TME) is a complex ecosystem that includes a variety of cellular components, each playing a significant role in tumor biology. The primary cellular constituents of the TME consist of tumor cells, immune cells, stromal cells, and endothelial cells, all of which interact dynamically to influence tumor progression and response to therapies.[146.1] The tumor microenvironment (TME) is a dynamic ecosystem surrounding a tumor, shaped by tumor cells and characterized by a diverse composition that includes immune cells such as T cells, B cells, macrophages, natural killer cells, neutrophils, and dendritic cells, as well as stromal cells like endothelial cells, fibroblasts, adipocytes, and stellate cells.[137.1] Immune cells are critical components of the TME, exhibiting a complex relationship with tumor growth; they can either suppress or promote tumor progression depending on the context.[3.1] This duality is influenced by various factors, including persistent inflammation, which can arise from chronic infections and is a common mechanism underlying tumor formation in several cancer types.[3.1] Understanding the intricate interactions among these cellular components is essential for elucidating the role of the TME in cancer biology and its implications for therapeutic strategies. Stromal cells, particularly cancer-associated fibroblasts (CAFs), are another major component of the TME. They facilitate crosstalk between cancer cells and the surrounding stroma, influencing tumor behavior and therapeutic responses.[140.1] Additionally, adipocytes within the TME produce leptin, a hormone that can promote tumor progression by affecting cancer cell proliferation and modulating immune responses.[138.1] The tumor microenvironment (TME) is a complex ecosystem that encompasses not only tumor cells but also a diverse array of non-cancerous cells and components, including immune cells, stromal cells, endothelial cells, and cancer-associated fibroblasts (CAFs).[140.1] The composition of the TME varies between different tumor types, but it consistently features these hallmark components, which play critical roles in the pathogenesis of cancer.[138.1] The TME is embedded in an altered extracellular matrix (ECM) that influences tumor growth, progression, and response to therapy.[146.1] This intricate environment is not merely a passive backdrop; rather, it actively participates in tumor initiation, invasion, and metastasis, highlighting the importance of understanding the interactions between tumor cells and their surrounding cellular and molecular components.[140.1] The dynamic interplay within the TME is essential for the rational development of effective anti-cancer treatments, as it profoundly impacts therapeutic outcomes.[146.1] Understanding the intricate interactions among these cellular components is crucial for developing targeted therapies and improving patient outcomes in cancer treatment. The characterization of these components and their roles in tumor biology is an active area of research, highlighting the shift from a cancer-centric model to a TME-centric approach in cancer therapy.[2.1]Extracellular Matrix and Soluble Factors
The extracellular matrix (ECM) and soluble factors within the tumor microenvironment (TME) play critical roles in tumor progression, metastasis, and therapeutic responses. The ECM is not merely a structural scaffold; it actively influences tumor cell behavior through various mechanisms. For instance, growth factors and chemokines that are tethered to and released from the ECM contribute to a tumor-supporting environment, facilitating processes such as cell migration and invasion.[170.1] Additionally, the ECM can be remodeled by cancer-associated fibroblasts (CAFs), which secrete large amounts of ECM components, thereby creating a supportive matrix that enhances tumor growth.[173.1] The interaction between tumor cells and the ECM is complex and dynamic. Cancer cells can modify the ECM through the secretion of factors that activate stromal cells, leading to the differentiation of these cells into CAFs. These CAFs, in turn, remodel the ECM by depositing proteins such as fibronectin and tenascin C, which are crucial for maintaining the tumor's structural integrity and promoting its invasive capabilities.[173.1] Moreover, the stiffness of the ECM has been shown to influence the expression of immune checkpoint proteins like PD-L1 in lung cancer cells, thereby modulating the anti-tumor immune response.[172.1] The tumor microenvironment (TME) is a complex ecosystem that includes both cellular components, such as stromal cells, and non-cellular components, such as the extracellular matrix (ECM). These dynamic interactions are essential for promoting cancer cell heterogeneity, clonal evolution, and multidrug resistance, ultimately leading to cancer progression and metastasis.[156.1] Targeting the TME offers a significant therapeutic advantage over directly targeting cancer cells, as the latter often exhibit genomic instability and are prone to drug resistance. In contrast, non-tumor cells within the TME tend to be more genetically stable and thus more vulnerable to therapeutic interventions.[158.1] Furthermore, understanding the various factors within the TME and their roles in facilitating tumor immune evasion is crucial for developing effective therapeutic strategies that can enhance cancer treatment outcomes.[166.1] By integrating this knowledge, researchers can devise novel strategies to disrupt the interplay between cancer cells and their microenvironment, contributing to the development of efficient and safe cancer therapies.[156.1]In this section:
Interactions Within The Tumor Microenvironment
Cancer Cell Interactions
The tumor microenvironment (TME) is a complex network of heterogeneous stromal cells, including cancer cells, cancer-associated fibroblasts (CAFs), endothelial cells, immune cells, and the extracellular matrix (ECM), which collectively influence cancer development and progression.[180.1] These components interact through reciprocal paracrine signaling, which can reshape the TME in ways that promote tumor growth.[178.1] Notably, cancer-associated fibroblasts and immune cells within the TME are known to influence each other, potentially altering the overall phenotype of the tumor and impacting responses to therapy.[181.1] This intricate interplay among various cell types underscores the critical role of the TME in cancerogenesis and the adaptation of cancer cells.[180.1] The ECM itself plays a pivotal role in modulating tumor behavior. Its structural and biochemical properties, such as stiffness and composition, significantly influence cancer cell interactions and can drive malignant transformation, invasion, and treatment resistance.[184.1] Alterations in cell-ECM interactions during tumor progression are critical, as they can enhance the ability of cancer cells to invade surrounding tissues and metastasize.[184.1] Additionally, tumor-associated hypoxia can induce changes in ECM composition, further promoting malignancy.[184.1] Cancer-associated fibroblasts (CAFs) are a heterogeneous population of stromal cells that play a crucial role in shaping the tumor microenvironment (TME) and influencing cancer progression.[193.1] These activated CAFs secrete various factors that promote tumor growth, angiogenesis, invasion, and metastasis, as well as contribute to extracellular matrix (ECM) remodeling and chemoresistance.[192.1] The TME is a complex ecosystem that includes not only CAFs but also diverse immune cell types, tumor cells, and other stromal components, all of which interact dynamically to affect tumor biology.[197.1] Importantly, CAFs and immune cells engage in reciprocal interactions that can alter tumor phenotypes and influence therapeutic responses.[181.1] Understanding these intricate relationships within the TME is essential for elucidating the etiology of cancer and developing more effective therapeutic strategies to overcome resistance to existing treatments.[197.1]Immune Cell Dynamics
The tumor microenvironment (TME) is a complex ecosystem where immune cells play pivotal roles in influencing tumor growth and metastasis. Various immune cell types, including tumor-associated macrophages (TAMs), T cells, and neutrophils, can either suppress or promote tumor progression depending on their activation state and the signals they receive from the tumor and its surroundings.[186.1] This dynamic interplay between neoplastic cells and the immune microenvironment regulates every step of the metastatic process, with immune cells contributing to invasion by secreting inflammatory factors that promote epithelial-to-mesenchymal transition and stroma remodeling.[188.1] TAMs, a significant component of the TME, are involved in tumor progression, metastasis, and angiogenesis. They can phagocytose pathogens and activate other immune cells, thereby influencing the tumor's immune landscape.[189.1] The TME also includes cancer-associated fibroblasts and endothelial cells, which interact with immune cells to shape cancer progression and therapy response.[219.1] Understanding these interactions is crucial for developing effective anti-cancer treatments, particularly immunotherapies, as they can restore immune control over tumors and achieve durable clinical responses.[220.1] The interactions between tumor cells and various immune cells have been characterized, revealing the involvement of specific ligand-receptor interactions across 14 different types of immune cells.[221.1] This characterization is crucial for understanding the complexities of the tumor microenvironment (TME) and its implications for immunotherapy development. In particular, the mesenchymal subtype of glioblastoma is believed to be influenced by both intrinsic alterations within cancer cells and extrinsic interactions with the TME, although these dynamics remain poorly understood.[223.1] Overall, the intricate relationships between immune cells and tumor cells highlight the significance of the TME in cancer biology and the potential for tailored therapeutic strategies.Therapeutic Resistance
Mechanisms of Resistance
Therapeutic resistance in cancer is significantly influenced by the tumor microenvironment (TME), which plays a crucial role in promoting multidrug resistance (MDR) through various mechanisms. One of the primary ways the TME contributes to resistance is by inhibiting the immune clearance of tumor cells, thereby facilitating immune escape responses.[229.1] This is achieved through the modulation of immunosuppressive cell populations, including tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), which alter the immune landscape to favor tumor survival and growth.[231.1] Additionally, tumors can switch the phenotype and function of normal immune cells from a potentially tumor-reactive state to one that supports tumor progression, further enhancing their ability to evade immune surveillance.[232.1] These interactions within the TME not only promote immune evasion but also stimulate the release of soluble paracrine factors that enhance tumor survival and growth, thereby complicating treatment strategies.[229.1] The tumor microenvironment (TME) plays a critical role in promoting therapeutic resistance in cancer cells through various mechanisms. One significant mechanism involves the stimulation of soluble paracrine factors that enhance tumor cell survival and growth, thereby contributing to multidrug resistance (MDR).[229.1] Cancer-associated fibroblasts (CAFs), as key components of the TME, are instrumental in this process. They facilitate the acquisition of malignant behaviors in cancer cells, including malignant proliferation, epithelial to mesenchymal transition (EMT), and the development of cancer-stem-like properties.[227.1] Additionally, CAFs can confer drug resistance by releasing paracrine survival factors or by activating pathways that lead to the expansion of therapy-resistant tumor-initiating cells, ultimately resulting in decreased chemosensitivity.[230.1] Thus, the interplay between the TME and CAFs is crucial in understanding the mechanisms underlying therapeutic resistance in cancer. The tumor microenvironment (TME) plays a critical role in the development of therapeutic resistance in cancer. It is characterized by complex interactions between cancer cells and various components, including stromal cells and the extracellular matrix (ECM), which contribute to the heterogeneity of cancer and promote multidrug resistance.[229.1] The TME can inhibit immune clearance of tumor cells, facilitate immune escape, and stimulate the release of soluble factors that enhance tumor survival and growth.[229.1] Additionally, metabolic reprogramming within the TME can alter drug delivery and absorption, further complicating treatment efficacy.[229.1] Changes in the ECM and surrounding vasculature can obstruct drug penetration, which is a significant barrier to effective therapy.[229.1] Furthermore, the ECM can influence the behavior of tumor-associated macrophages (TAMs), which are associated with poor prognosis in various cancers, indicating that targeting the ECM may improve immune responses and therapeutic outcomes.[228.1] Overall, understanding the mechanisms by which the TME contributes to drug resistance is essential for developing effective therapeutic strategies.[237.1]Strategies to Overcome Resistance
The tumor microenvironment (TME) presents significant challenges to effective cancer treatment, primarily due to its immunosuppressive characteristics. To address these challenges, various strategies are being explored to overcome resistance mechanisms within the TME. One prominent approach involves targeting myeloid-derived suppressor cells (MDSCs), which are the main type of immunosuppressive cells in cancer. Strategies include depleting MDSC populations by targeting specific markers such as VEGFR and CD33, blocking their migration into the TME through CCR2 or CXCR1/2 inhibition, and inhibiting their activity via pathways involving PGE2 and IDO.[233.1] Additionally, enhancing the immune system's antitumor response is crucial for transforming "cold" tumors into "hot" tumors. Current strategies focus on three main objectives: boosting the immune system through adaptive T-cell therapies and cancer vaccines, and reversing or blocking immunosuppressive factors using immune checkpoint blockade (ICB) therapies.[234.1] Reprogramming various facets of the TME is also a key strategy to counteract immunosuppression. This includes addressing abnormal blood vessels, myeloid cells, and regulatory T cells (Tregs), with the aim of incorporating these emerging strategies into clinical approaches to overcome microenvironment-driven resistance mechanisms to immunotherapy.[235.1] Moreover, targeting specific signaling pathways within the TME can enhance the efficacy of existing cancer treatments. For instance, the NF-κB pathway has been identified as a critical target; however, challenges such as low efficacy and the development of drug resistance have been noted.[256.1] Similarly, cytokine and chemokine signaling pathways, particularly those involving TGF-β, play significant roles in facilitating cancer immune escape by interacting with various immune cells.[257.1] Nanomedicine is another promising avenue for modifying the TME to enhance therapeutic efficacy. Strategies include utilizing nanoparticles to improve oxygen delivery, activate immune responses, and reduce immunosuppression within tumors.[259.1] These approaches aim to optimize the TME, thereby promoting T-cell activation and enhancing the overall antitumor immune response.[257.1]Future Directions
Emerging Research Areas
Emerging research areas in the tumor microenvironment (TME) are increasingly focusing on the complex interactions between cancer cells and their surrounding milieu, which significantly influence cancer progression and therapeutic responses. One promising avenue is the development of tumor-on-a-chip technology, which accurately replicates the TME and predicts physiological responses to anti-cancer therapies, thereby serving as a vital translational tool for enhancing cancer research and drug development.[274.1] Additionally, there is a growing interest in stromal reprogramming techniques aimed at altering the TME to improve the efficacy of existing cancer therapies. For instance, targeting signaling pathways related to stromal reprogramming, such as those involving TGF-β, has been identified as a potential strategy to enhance treatment outcomes by addressing the heterogeneity of the TME.[276.1] Research has also highlighted the role of tumor-infiltrating immune cells in inducing epigenetic alterations that affect both stromal and tumor cells, thereby impacting disease outcomes.[281.1] The interplay between different immune cell types within the tumor microenvironment (TME) significantly influences the effectiveness of current cancer therapies. Immune cells' metabolism plays a crucial role in their differentiation and function, and a complex interplay of environmental factors within the TME can profoundly impact these metabolic activities.[282.1] This has led to an emerging interest in advancing our understanding of the diverse metabolic phenotypes present in the TME. Furthermore, the interactions between cancer and the immune TME are critical, as they influence the outcomes of immunotherapy and various other anti-cancer therapies.[280.1] Understanding these dynamics is essential for developing innovative strategies to enhance therapeutic responses. Finally, the integration of TME research into clinical practice is gaining traction, with advances in molecular technologies enabling detailed genomic and transcriptional analyses of both cancer cells and the TME. This integration aims to identify novel therapeutic targets and enhance patient outcomes by shifting from a cancer-centric model to a TME-centric approach in cancer treatment.[286.1] As research continues to evolve, these emerging areas hold promise for developing more effective cancer therapies that consider the intricate dynamics of the tumor microenvironment.Potential Therapeutic Targets
The tumor microenvironment (TME) is a multifaceted network where cancer cells interact with stromal and immune cells, significantly influencing tumor progression and resistance to therapies. Recent insights into these interactions have identified specific therapeutic targets within the TME that hold promise for enhancing cancer treatment outcomes. Cancer-associated fibroblasts (CAFs), particularly those expressing fibroblast activation protein (FAP), are pivotal in the TME. These FAP-positive CAFs secrete factors like CXCL12, which shield pancreatic ductal adenocarcinoma (PDAC) cells from immune attacks, rendering them less responsive to immune checkpoint inhibitors [293.1]. Targeting CAFs and their secretions is being explored to improve the efficacy of existing therapies and counteract resistance mechanisms [290.2]. Myeloid-derived suppressor cells (MDSCs), including macrophages, dendritic cells, and myeloid precursors, are crucial in promoting tumor growth by suppressing T cell and natural killer (NK) cell activity through cytokines such as IL-6, IL-10, and TGF-β. These cells can also transform into tumor-associated macrophages (TAMs) under hypoxic conditions, further supporting tumor progression [308.1]. By understanding and targeting these immune components, novel strategies can be developed to modify immune responses and bolster anti-tumor immunity [307.1]. The extracellular matrix (ECM) is another critical TME component, influencing tumor cell behavior and therapeutic responses. Disrupting ECM-tumor cell interactions could impair tumor growth and metastasis, offering another avenue for therapeutic intervention [292.1]. Given the dynamic nature of the TME, a comprehensive therapeutic approach is essential. This involves designing agents that target not only cancer cells but also the surrounding stromal and immune cells, as their interactions significantly impact treatment outcomes [291.1]. By focusing on these specific targets within the TME, there is potential to develop more effective cancer therapies that address the complexities of tumor biology and resistance [290.1][308.2].In this section:
References
[1] Tumor microenvironment - Wikipedia — The tumor microenvironment is a complex ecosystem surrounding a tumor, composed of cancer cells, stromal tissue (including blood vessels, immune cells, fibroblasts and signaling molecules) and the extracellular matrix. Mutual interaction between cancer cells and the different components of the tumor microenvironment support its growth and invasion in healthy tissues which correlates with tumor resistance to current treatments and poor prognosis. Tumor-associated immune cells in the tumor microenvironment (TME) of breast cancer models Tumor-associated immune cells in the tumor microenvironment (TME) of breast cancer models "Stromal cells in tumor microenvironment and breast cancer". "Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy".
[2] Tumor microenvironment components: Allies of cancer progression ... — The tumor microenvironment is composed of diverse components, and it is essential to understand the interactions between tumor cells and these components, aiming for improved therapies . Thus, the characterization of these stromal components becomes important to allow for the development of new therapeutic strategies that are more targeted
[3] The tumor microenvironment: Current Biology - Cell Press — Immune cells are critical components of the tumor microenvironment. Depending on the context, a dichotomy exists in the relationship between immune cells and the tumor microenvironment: immune cells can either suppress tumor growth or promote it ().Persistent inflammation due to chronic infection is a common mechanism underlying tumor formation in several types of cancer, including colorectal
[4] Tumor Microenvironment: Key Components and Molecular Pathways — Key processes such as angiogenesis (formation of new blood vessels), hypoxia (low oxygen levels), and chronic inflammation drive tumor growth, metastasis, and resistance to treatments. Cellular Components of the Tumor Microenvironment. The tumor microenvironment (TME) is composed of various cellular players that interact to influence cancer progression and therapy responses.
[5] The tumor microenvironment - PubMed — The tumor microenvironment - PubMed A tumor is not simply a group of cancer cells, but rather a heterogeneous collection of infiltrating and resident host cells, secreted factors and extracellular matrix. The composition of the tumor microenvironment varies between tumor types, but hallmark features include immune cells, stromal cells, blood vessels, and extracellular matrix. It is believed that the "tumor microenvironment is not just a silent bystander, but rather an active promoter of cancer progression" (Truffi et al., 2020). The role of immune cells in the TME can be to either suppress tumor formation (anti-tumor microenvironment) or promote tumorigenesis (immune suppressive microenvironment). Tumor-associated stromal cells as key contributors to the tumor microenvironment. Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy.
[6] Tumor Microenvironment - an overview | ScienceDirect Topics — Tumor microenvironment. The role of the microenvironment during the initiation and progression of malignancy is appreciated to be of critical importance for improved molecular diagnostics and therapeutics. 1 The tumor microenvironment is the product of crosstalk between different cells types. For instance, in epithelial tumors, these cells include the invasive carcinoma and its stromal elements.
[7] Epigenetic interplay between immune, stromal and cancer cells in the ... — In the tumor microenvironment, tumor-infiltrating immune cells play a crucial role inducing epigenetic alterations in both stroma and tumor cells which finally will impact the outcome of the disease. In fact, several studies have shown that chronic inflammation increases the risk of cancer and promotes tumor progression [ 43 , 44 ].
[8] Unraveling the tumor microenvironment: Insights into cancer metastasis ... — Unraveling the tumor microenvironment: Insights into cancer metastasis and therapeutic strategies - ScienceDirect Dynamic TME Interactions: Cancer cells and the tumor microenvironment (TME) have an intricate relationship that impacts cancer progression and therapeutic responses. This comprehensive review delves into the pivotal role of the tumor microenvironment (TME) in cancer metastasis and therapeutic response, offering fresh insights into the intricate interplay between cancer cells and their surrounding milieu. Moreover, it investigates innovative therapeutic approaches aimed at targeting the TME, including stromal reprogramming, immune microenvironment modulation, extracellular matrix (ECM)-targeting agents, and personalized medicine strategies, highlighting their potential to augment treatment outcomes. Next article in issue No articles found. For all open access content, the relevant licensing terms apply.
[9] Tumor microenvironment complexity and therapeutic implications at a ... — Tumor microenvironment complexity and therapeutic implications at a glance | Cell Communication and Signaling | Full Text Search all BMC articles Tumor microenvironment complexity and therapeutic implications at a glance Tumor microenvironment complexity and therapeutic implications at a glance The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer.
[10] Understanding the tumor immune microenvironment (TIME) for effective ... — Reciprocal interactions between tumor and associated immune and stromal cell types evolve as the tumor grows, thus allowing for modulation of both tumor cell intrinsic and extrinsic processes 37
[12] Epigenetic interplay between immune, stromal and cancer cells in the ... — In the tumor microenvironment, tumor-infiltrating immune cells play a crucial role inducing epigenetic alterations in both stroma and tumor cells which finally will impact the outcome of the disease. In fact, several studies have shown that chronic inflammation increases the risk of cancer and promotes tumor progression .
[18] Role of the Immune Component of Tumor Microenvironment in the ... — Moreover, cancer cells in solid tumors are surrounded by cellular and molecular microenvironment that actively influences tumor cell behavior. Local tumor microenvironment (TME) consisting of immune cells with diverse phenotypes and functions strongly contributes to intratumor heterogeneity and modulates responses to treatment.
[19] The updated landscape of tumor microenvironment and drug ... - Nature — Advertisement The updated landscape of tumor microenvironment and drug repurposing Signal Transduction and Targeted Therapy volume 5, Article number: 166 (2020) Cite this article 46k Accesses 450 Citations 29 Altmetric Metrics details Subjects Abstract Accumulating evidence shows that cellular and acellular components in tumor microenvironment (TME) can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Cancer research and treatment have switched from a cancer-centric model to a TME-centric one, considering the increasing significance of TME in cancer biology. Herein, we present an updated image of TME with emphasis on hypoxic niche, immune microenvironment, metabolism microenvironment, acidic niche, innervated niche, and mechanical microenvironment. This review depicts a comprehensive and vivid landscape of TME from biology to treatment.
[51] A history of exploring cancer in context - PubMed — The concept that progression of cancer is regulated by interactions of cancer cells with their microenvironment was postulated by Stephen Paget over a century ago. Contemporary tumour microenvironment (TME) research focuses on the identification of tumour-interacting microenvironmental constituents, …
[52] Tumor microenvironment - Wikipedia — The tumor microenvironment is a complex ecosystem surrounding a tumor, composed of cancer cells, stromal tissue (including blood vessels, immune cells, fibroblasts and signaling molecules) and the extracellular matrix. Mutual interaction between cancer cells and the different components of the tumor microenvironment support its growth and invasion in healthy tissues which correlates with tumor resistance to current treatments and poor prognosis. Tumor-associated immune cells in the tumor microenvironment (TME) of breast cancer models Tumor-associated immune cells in the tumor microenvironment (TME) of breast cancer models "Stromal cells in tumor microenvironment and breast cancer". "Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy".
[53] The evolving tumor microenvironment: From cancer initiation to ... - PubMed — PMID: 36917948 DOI: 10.1016/j.ccell.2023.02.016 Item in Clipboard Full text links Cite Display options Display options Format Abstract Cancers represent complex ecosystems comprising tumor cells and a multitude of non-cancerous cells, embedded in an altered extracellular matrix. The tumor microenvironment (TME) includes diverse immune cell types, cancer-associated fibroblasts, endothelial cells, pericytes, and various additional tissue-resident cell types. These host cells were once considered bystanders of tumorigenesis but are now known to play critical roles in the pathogenesis of cancer. Here, we review the importance of the TME in each stage of cancer progression, from tumor initiation, progression, invasion, and intravasation to metastatic dissemination and outgrowth. Understanding the complex interplay between tumor cell-intrinsic, cell-extrinsic, and systemic mediators of disease progression is critical for the rational development of effective anti-cancer treatments.
[54] The Importance of the Tumor Microenvironment to Understand Tumor Origin ... — During the second half of the twentieth century, oncology adopted a tumor-centric approach to cancer treatment, focusing primarily on the tumor cell to identify new therapeutic targets [].However, since the 2000s, we have seen a gradual shift in this paradigm with numerous studies highlighting the importance of the tumor microenvironment in tumor progression, patient prognosis, and therapy
[55] The updated landscape of tumor microenvironment and drug ... - Nature — Advertisement The updated landscape of tumor microenvironment and drug repurposing Signal Transduction and Targeted Therapy volume 5, Article number: 166 (2020) Cite this article 46k Accesses 450 Citations 29 Altmetric Metrics details Subjects Abstract Accumulating evidence shows that cellular and acellular components in tumor microenvironment (TME) can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Cancer research and treatment have switched from a cancer-centric model to a TME-centric one, considering the increasing significance of TME in cancer biology. Herein, we present an updated image of TME with emphasis on hypoxic niche, immune microenvironment, metabolism microenvironment, acidic niche, innervated niche, and mechanical microenvironment. This review depicts a comprehensive and vivid landscape of TME from biology to treatment.
[56] Tumor microenvironment and cancer metastasis: molecular mechanisms and ... — Abstract. The tumor microenvironment (TME) plays a crucial role in cancer development and metastasis. This review summarizes the current research on how the TME promotes metastasis through molecular pathways, focusing on key components, such as cancer-associated fibroblasts, immune cells, endothelial cells, cytokines, and the extracellular matrix.
[57] The Role of the Tumor Microenvironment (TME) in Advancing Cancer ... - MDPI — Understanding how different contributors within the tumor microenvironment (TME) function and communicate is essential for effective cancer detection and treatment. The TME encompasses all the surroundings of a tumor such as blood vessels, fibroblasts, immune cells, signaling molecules, exosomes, and the extracellular matrix (ECM). Subsequently, effective cancer therapy relies on addressing
[59] Personalized Medicine: Recent Progress in Cancer Therapy — Personalized medicine (PM) or precision medicine in oncology is an emerging approach for tumor treatment and prevention that takes into account inter- and intra-tumor variability in genes, tumor (immune) environment, and lifestyle and morbidities of each person diagnosed with cancer. Colorectal cancer is a frequently used and well-known model in which tumor-tailored treatment has already been implemented. To optimize patient- and tumor-tailored treatments in patients with breast cancer, Mazo et al. In addition to the use of molecular characteristics of tumor cells, clinical tumor features can also be valuable biomarkers, thereby guiding patient- and tumor-tailored treatment. use tumor features for tailored treatment in patients with large B-cell lymphoma.
[60] Unraveling the tumor microenvironment: Insights into cancer metastasis ... — Unraveling the tumor microenvironment: Insights into cancer metastasis and therapeutic strategies - ScienceDirect Dynamic TME Interactions: Cancer cells and the tumor microenvironment (TME) have an intricate relationship that impacts cancer progression and therapeutic responses. This comprehensive review delves into the pivotal role of the tumor microenvironment (TME) in cancer metastasis and therapeutic response, offering fresh insights into the intricate interplay between cancer cells and their surrounding milieu. Moreover, it investigates innovative therapeutic approaches aimed at targeting the TME, including stromal reprogramming, immune microenvironment modulation, extracellular matrix (ECM)-targeting agents, and personalized medicine strategies, highlighting their potential to augment treatment outcomes. Next article in issue No articles found. For all open access content, the relevant licensing terms apply.
[63] Single-Cell Informatics for Tumor Microenvironment and Immunotherapy - MDPI — Cancer comprises malignant cells surrounded by the tumor microenvironment (TME), a dynamic ecosystem composed of heterogeneous cell populations that exert unique influences on tumor development. The immune community within the TME plays a substantial role in tumorigenesis and tumor evolution. The innate and adaptive immune cells "talk" to the tumor through ligand-receptor interactions
[65] Enhancing immuno-oncology investigations through ... - Cell Press — This advancement has enabled the discovery of previously unknown rare cell types, elucidation of cellular composition, characterization of cell interactions within tumor tissues, and construction of increasingly detailed single-cell atlases of tumors. 35 To leverage the insights gained from single-cell analysis, IOBR 2.0 has updated its single
[68] The tumor microenvironment is an ecosystem sustained by ... - Cell Press — Cancer-associated fibroblasts and immune cells are known to interact within the tumor microenvironment and influence each other to impact on tumor progression. Here, Kay et al. discuss how they can also potentially metabolically interact with each other to alter the overall phenotype of the tumor and influence response to therapy.
[70] Tumor microenvironment: A playground for cells from multiple diverse ... — The cross-talk between different cells in the TME leads to cell activation, differentiation and alterations in the structural and biological properties of ECM, which aids in proliferation, invasion and metastatic potential of tumor cells . These interactions between the cells and their microenvironment aid in tumor development, protection
[71] Immune cells within the tumor microenvironment: Biological functions ... — Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy - ScienceDirect Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy The roles of the immune cells in cancer immunotherapy. Here, we review the biological functions of immune cells within TME and their roles in cancer immunotherapy, and discuss the perspectives of the basic studies for improving the effectiveness of the clinical use. In this review, we discuss the roles of these tumor associated immune cells in TME and highlight their application in cancer immunotherapy. CD4(+) T cell help in cancer immunology and immunotherapy Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives
[98] The tumor microenvironment - PubMed — The tumor microenvironment - PubMed A tumor is not simply a group of cancer cells, but rather a heterogeneous collection of infiltrating and resident host cells, secreted factors and extracellular matrix. The composition of the tumor microenvironment varies between tumor types, but hallmark features include immune cells, stromal cells, blood vessels, and extracellular matrix. It is believed that the "tumor microenvironment is not just a silent bystander, but rather an active promoter of cancer progression" (Truffi et al., 2020). The role of immune cells in the TME can be to either suppress tumor formation (anti-tumor microenvironment) or promote tumorigenesis (immune suppressive microenvironment). Tumor-associated stromal cells as key contributors to the tumor microenvironment. Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy.
[99] Tumor microenvironment: recent advances in understanding and its role ... — Tumor microenvironment: recent advances in understanding and its role in modulating cancer therapies | Medical Oncology Oncogene-driven changes in tumor cell metabolism can impact the TME to limit immune responses and present barriers to cancer therapy. Tumor cell-targeting and tumor microenvironment-responsive nanoplatforms for the multimodal imaging-guided photodynamic/photothermal/chemodynamic treatment of cervical cancer. Stromal cells in tumor microenvironment and breast cancer. https://doi.org/10.3390/cancers16030626. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Peng S, Wang H, Xin Y, Zhao W, Zhan M, Li J, et al. Tumor-microenvironment-responsive nanomedicine for enhanced cancer immunotherapy. https://doi.org/10.3390/cancers14133170.
[100] Tumor microenvironment as a complex milieu driving cancer ... - Springer — The characteristic communication between tumor cells and their microenvironment is bidirectional , wherein tumor cells can reprogram the TME to support their own growth and survival, while components of the TME can influence the genetic and epigenetic landscape of tumor cells, thereby facilitating the evolution of cancer heterogeneity and drug resistance . As integral components of the TME, tumor microbiota participate in cancer pathophysiology by enhancing oncogenic signals, modulating tumor metabolism, fostering an immunosuppressive microenvironment, and inducing chronic inflammation through various pathways, including enzymatic activity, toxin release, and metabolite generation . Targeting T cell metabolism in the tumor microenvironment: an anti-cancer therapeutic strategy. Editorial: The intricate innate immune-cancer cell relationship in the context of tumor angiogenesis, immunity and microbiota: the angiogenic switch in the tumor microenvironment as a key target for immunotherapies.
[103] Nanobodies targeting the tumor microenvironment and their formulation ... — Nanobodies targeting the tumor microenvironment and their formulation as nanomedicines | Molecular Cancer | Full Text Depending on the specific cancer diagnosis, patients can benefit from a range of targeted or immunotherapeutic approaches, including antibody–drug conjugates, immune checkpoint inhibitors, adoptive cell transfer, cytokine therapies, and therapeutic vaccines, among others. Various immune, stromal, vascular and cancer cell molecules, as well as components of the extracellular matrix (ECM) have been assessed as therapeutic targets for nanobody-based therapies. This article reviews recent advances in the use of nanobodies to target cancer cells, immune cells, and stromal elements of the TME. We will also discuss the advantages of nanoparticles and the use of nanobody-based nanoparticle formulations for targeted drug delivery and therapeutic development, highlighting the potential for these technologies to revolutionize cancer treatment.
[105] The updated landscape of tumor microenvironment and drug ... - Nature — Advertisement The updated landscape of tumor microenvironment and drug repurposing Signal Transduction and Targeted Therapy volume 5, Article number: 166 (2020) Cite this article 46k Accesses 450 Citations 29 Altmetric Metrics details Subjects Abstract Accumulating evidence shows that cellular and acellular components in tumor microenvironment (TME) can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Cancer research and treatment have switched from a cancer-centric model to a TME-centric one, considering the increasing significance of TME in cancer biology. Herein, we present an updated image of TME with emphasis on hypoxic niche, immune microenvironment, metabolism microenvironment, acidic niche, innervated niche, and mechanical microenvironment. This review depicts a comprehensive and vivid landscape of TME from biology to treatment.
[106] Tumor microenvironment as a therapeutic target in cancer — Tumor microenvironment as a therapeutic target in cancer - PMC There is a significant therapeutic advantage in targeting the TME compared with directly targeting cancer cells, because cancer cells are prone to drug resistance due to their genomic instability, whereas non-tumor cells in the TME have a genetically more stable nature and are more vulnerable. For example, fibroblast activation protein (FAP)-positive CAFs secrete CXCL12, which protected PDAC cancer cells from anti-tumor T-cells and caused unresponsiveness to immune checkpoint blockade (ICB) therapies in mouse PDAC models30. Cancer Cell 28, 831–833, doi: 10.1016/j.ccell.2015.11.002 (2015). Cancer Cell 25, 735–747, doi: 10.1016/j.ccr.2014.04.021 (2014). Cancer Cell 16, 173–174, doi: 10.1016/j.ccr.2009.08.014 (2009). Cancer Cell 32, 42–56 e46, doi: 10.1016/j.ccell.2017.06.003 (2017).
[107] Novel insights into tumor microenvironment and gastric cancer therapy — Their study findings, published in Cancer Discovery, bring scientists closer to developing new treatments that can be customised according to the specific characteristics of a patient's tumor, to
[108] Immunotherapy and tumor microenvironment - PMC — A positive response to immunotherapy usually relies on dynamic interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). Depending on the context of these interactions, the TME may play important roles to either dampen or enhance immune responses.
[110] Deciphering functional tumor-immune crosstalk through highly ... — The tumor microenvironment (TME) is a complex ecosystem where cancer cells dynamically interact with diverse non-malignant cells, including immune cells, fibroblasts, and endothelial cells, as well as the extracellular matrix. 1 These intricate interactions shape cancer progression and therapy response. 2 In particular, crosstalk between cancer cells and immune cells within the TME plays a
[111] Exploring the Tumor Immune Microenvironment: Key Insights and Therapies — Facebook Instagram Linkedin Pinterest Immune Cells and Their Roles in the Tumor Immune Microenvironment T-Cells in the Tumor Immune Microenvironment Targeting the Tumor Immune Microenvironment in Cancer Therapy Immune Cells and Their Roles in the Tumor Immune Microenvironment T-Cells in the Tumor Immune Microenvironment Targeting the Tumor Immune Microenvironment in Cancer Therapy Combining checkpoint inhibitors with anti-angiogenic therapies can normalize the tumor vasculature, improving immune cell infiltration. The tumor immune microenvironment (TIME) presents both opportunities and challenges in advancing cancer therapy. Techniques like single-cell RNA sequencing reveal interactions between tumor and immune cells, guiding the choice of immune checkpoint inhibitors, CAR-T therapies, or combination approaches. The tumor immune microenvironment plays a pivotal role in cancer progression and therapy response.
[121] Tumor microenvironment complexity and therapeutic implications at a ... — Tumor microenvironment complexity and therapeutic implications at a glance | Cell Communication and Signaling | Full Text Search all BMC articles Tumor microenvironment complexity and therapeutic implications at a glance Tumor microenvironment complexity and therapeutic implications at a glance The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer.
[123] From complexity to clarity: unravelling tumor heterogeneity ... - Springer — In recent years, the emergence of high-throughput technologies has advanced our understanding of the variables influencing tumor heterogeneity beyond intrinsic tumor characteristics. Emerging knowledge shows that drivers of tumor heterogeneity are not only intrinsic to cancer cells but can also emanate from their microenvironment, which
[124] Functional heterogeneity of fibroblasts in primary tumors and ... — Cancer-associated fibroblasts (CAFs) are abundant components of the tumor microenvironment (TME) of most solid malignancies and have emerged as key regulators of cancer progression and therapy response. Although recent technological advances have uncovered substantial CAF molecular heterogeneity at the single-cell level, defining functional roles for most described CAF populations remains
[137] Measuring the composition of the tumor microenvironment with ... — The tumor microenvironment (TME) is the dynamic ecosystem surrounding a tumor, driven and shaped by tumor cells throughout their evolution [].In addition to tumor cells, the common composition of the TME also includes immune cells (T cells, B cells, macrophages, natural killer cells, neutrophils and dendritic cells), stromal cells (endothelial cells, fibroblasts, adipocytes and stellate cells
[138] Tumor Microenvironment - PMC — The composition of the TME varies between tumor types, but hallmark features include immune cells, stromal cells, blood vessels, and extracellular matrix (ECM). The anti-tumorigenic roles of B-cells, include antigen-presentation to T-cells, anti-tumor antibody production and secretion of cytokines that promote cytotoxic immune responses (e.g. IFN-γ). Regulatory B-cells promote tumor aggression through production of cytokines (e.g. IL-10 and transforming growth factor-beta (TGF-β)) that promote immune suppressive phenotypes in macrophages, neutrophils and cytotoxic T cells. Cancer associated fibroblasts (CAFs) are a major component of the tumor stroma and play a critical role in facilitating crosstalk between cancer cells and TME. Leptin is an important hormone produced by adipocytes and promotes tumor progression directly by influencing breast cancer cell proliferation and indirectly by activation of macrophages.
[140] The evolving tumor microenvironment: From cancer initiation to ... — PMID: 36917948 DOI: 10.1016/j.ccell.2023.02.016 Item in Clipboard Full text links Cite Display options Display options Format Abstract Cancers represent complex ecosystems comprising tumor cells and a multitude of non-cancerous cells, embedded in an altered extracellular matrix. The tumor microenvironment (TME) includes diverse immune cell types, cancer-associated fibroblasts, endothelial cells, pericytes, and various additional tissue-resident cell types. These host cells were once considered bystanders of tumorigenesis but are now known to play critical roles in the pathogenesis of cancer. Here, we review the importance of the TME in each stage of cancer progression, from tumor initiation, progression, invasion, and intravasation to metastatic dissemination and outgrowth. Understanding the complex interplay between tumor cell-intrinsic, cell-extrinsic, and systemic mediators of disease progression is critical for the rational development of effective anti-cancer treatments.
[146] Deciphering the tumour immune microenvironment cell by cell — Tumour growth, progression and response to therapy are profoundly influenced by the dynamic and complex composition of the tumour microenvironment (TME). Apart from the cancer cells, the TME comprises different cellular components including stromal cells, endothelial cells and immune cells, as well as non-cellular components such as growth factors, cytokines and metabolites, which collectively
[156] Tumor microenvironment complexity and therapeutic implications at a ... — Tumor microenvironment complexity and therapeutic implications at a glance | Cell Communication and Signaling | Full Text Search all BMC articles Tumor microenvironment complexity and therapeutic implications at a glance Tumor microenvironment complexity and therapeutic implications at a glance The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer.
[158] Tumor microenvironment as a therapeutic target in cancer — Tumor microenvironment as a therapeutic target in cancer - PMC There is a significant therapeutic advantage in targeting the TME compared with directly targeting cancer cells, because cancer cells are prone to drug resistance due to their genomic instability, whereas non-tumor cells in the TME have a genetically more stable nature and are more vulnerable. For example, fibroblast activation protein (FAP)-positive CAFs secrete CXCL12, which protected PDAC cancer cells from anti-tumor T-cells and caused unresponsiveness to immune checkpoint blockade (ICB) therapies in mouse PDAC models30. Cancer Cell 28, 831–833, doi: 10.1016/j.ccell.2015.11.002 (2015). Cancer Cell 25, 735–747, doi: 10.1016/j.ccr.2014.04.021 (2014). Cancer Cell 16, 173–174, doi: 10.1016/j.ccr.2009.08.014 (2009). Cancer Cell 32, 42–56 e46, doi: 10.1016/j.ccell.2017.06.003 (2017).
[166] Tumor microenvironment: Nurturing cancer cells for immunoevasion and ... — We will delve into various factors within the TME and their roles in facilitating tumor immune evasion. By integrating current knowledge, this review aims to deepen our understanding of the intricate relationship between cancer cells and their microenvironment, providing new insights into therapeutic interventions to enhance cancer treatment.
[170] The extracellular matrix in tumor progression and metastasis — The extracellular matrix in tumor progression and metastasis - PubMed Search in PubMed Search in PubMed Growth factors and chemokines, which are tethered to and released from the ECM, as well as metabolic changes of the cells within the tumor bulk, add to the tumor-supporting tumor microenvironment. Moreover, primed by soluble factors of the primary tumor, the ECM of distant organs may be remodeled in a way to facilitate the engraftment of metastasizing cancer cells. Keywords: Cancer-associated fibroblast; Cell infiltration; Cell migration; Extracellular matrix; Invadopodia; Metastasis; Metastatic cascade; Metastatic niche; Tumor microenvironment; Tumor progression. Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis. Search in PubMed Search in PubMed Search in PubMed Search in PubMed Search in PubMed Search in PubMed Search in PubMed Search in PubMed Search in PubMed
[172] Extracellular matrix and its therapeutic potential for cancer treatment — Lung cancer cells also express more PD-L1 in response to ECM stiffness to shut down the anti-tumor immune response mediated by CD8+ T cells218. J. Hyaluronan-CD44 interaction promotes oncogenic signaling, microRNA functions, chemoresistance, and radiation resistance in cancer stem cells leading to tumor progression. R. The human hyaluronan receptor RHAMM is expressed as an intracellular protein in breast cancer cells. Ki26894, a novel transforming growth factor-beta type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Angiotensin II activates extracellular signal regulated kinases via protein kinase C and epidermal growth factor receptor in breast cancer cells.
[173] Concepts of extracellular matrix remodelling in tumour ... - Nature — Thus, it is not surprising that cancer cells and tumour-associated stromal cells modify all four ECM remodelling mechanisms, creating a cancer-supporting matrix that actively contributes to the pathology of the tumour (Fig. 2)12. a, b Tumour-derived factors activate stromal cells which differentiate into cancer-associated fibroblasts (CAFs) leading to the secretion and deposition of large amounts of ECM components along with the cancer cells. The tumour-derived activation factors induce the differentiation of stromal cells towards so-called cancer-associated fibroblasts (CAFs), which function as myofibroblasts and remodel the ECM to support tumour growth17,20,23,24. Stromal cells in the pre-metastatic niche are activated by tumour-derived factors and myofibroblasts remodel the ECM, for example, by the deposition of fibronectin, tenascin C, osteopontin, and versican depending on tissue context.
[178] Tumor microenvironment: Interactions and therapy - Wiley Online Library — Tumor microenvironment (TME) is a host for a complex network of heterogeneous stromal cells with overlapping or opposing functions depending on the dominant signals within this milieu. Reciprocal paracrine interactions between cancer cells with cells within the tumor stroma often reshape the TME in favor of the promotion of tumor.
[180] Tumor Microenvironment: Cellular Interaction and Metabolic Adaptations — The tumor microenvironment (TME) plays a critical role in cancerogenesis. Various components of the TME, such as cancer cells, cancer-associated fibroblasts (CAFs), endothelial cells (ECs), tumor-infiltrating immune cells, adipocytes, and the extracellular matrix (ECM), collectively influence cancer development, progression, and the adaptation of cancer cells, as well as their resistance to
[181] The tumor microenvironment is an ecosystem sustained by metabolic ... — Cancer-associated fibroblasts and immune cells are known to interact within the tumor microenvironment and influence each other to impact on tumor progression. Here, Kay et al. discuss how they can also potentially metabolically interact with each other to alter the overall phenotype of the tumor and influence response to therapy.
[184] Extracellular matrix in cancer progression and therapy - PMC — Keywords: cancer invasion, cancer metabolism, cancer progression, cancer therapy, cell-ECM interaction, extracellular matrix, metastasis During cancer progression, alterations in tumor cell – ECM interactions drive malignant transformation, invasion, and metastasis, as well as treatment resistance , , , , , . These excess ECM molecules come from the tumor cells and cancer-associated fibroblasts (CAFs) . Adding to the mix, tumor-associated hypoxia induces lysyl oxidase expression , along with other ECM modifying enzymes, resulting in the fibrillar collagen crosslinking within the ECM and the synergy of biophysical and biochemical changes that allow cancer cells to more efficaciously invade and metastasize . doi: 10.1016/j.cell.2016.01.043. doi: 10.4103/2153-3539.139707. doi: 10.1517/14728222.9.3.491. doi: 10.1158/0008-5472.can-06-0482. doi: 10.1038/s41568-018-0016-5. doi: 10.1038/s41573-019-0024-5. doi: 10.1038/s41568-020-00327-9. doi: 10.1186/1471-2407-12-4. doi: 10.1038/s41467-018-06893-9. doi: 10.1016/j.cell.2017.10.044.
[186] Tumor microenvironment and cancer metastasis: molecular mechanisms and ... — Immune cells within the TME, including macrophages, T cells, and neutrophils, can either suppress or promote tumor growth and metastasis, depending on their state of activation and the signals they receive from the tumor and its surroundings (Ramos et al., 2022). These metabolic changes support the anabolic growth of tumors, facilitate adaptation to hypoxic environments, and provide cancer cells with the necessary resources to evade immune responses and sustain metastatic potential (Nong et al., 2020). The molecular mechanisms through which the TME contributes to cancer metastasis are complex and multifaceted, involving alterations in cell signaling, ECM remodeling, immune modulation, angiogenesis, and metabolic reprogramming (Neophytou et al., 2021). Drugs like metformin, 2-Deoxyglucose, Telaglenastat, Ivosidenib, and Olutasidenib target the altered metabolism of cancer cells within the TME, disrupting key metabolic pathways to inhibit tumor growth (Xiao et al., 2023).
[188] The Immune Microenvironment and Cancer Metastasis — The dynamic interplay between neoplastic cells and the immune microenvironment regulates every step of the metastatic process. Immune cells contribute to invasion by secreting a cornucopia of inflammatory factors that promote epithelial-to-mesenchymal transition and remodeling of the stroma. Cancer …
[189] Myeloid cells are involved in tumor immunity, metastasis and ... - Springer — Tumor-associated macrophages (TAMs) Macrophages are part of the innate immune regulation and can phagocytose pathogens and digest cell debris. They can also activate other types of immune cells to resist the invasion of pathogens (Wang et al. 2022a).TAMs are an important component of the tumor microenvironment and participate in processes such as tumor progression, metastasis, and angiogenesis
[192] Regulation of cancer-associated fibroblasts for enhanced cancer ... — The tumor microenvironment (TME) is a complex and dynamic ecosystem that plays a critical role in cancer progression. It comprises various cell types, including immune cells, tumor cells, and stromal cells. Among these, cancer-associated fibroblasts (CAFs) represent a heterogeneous population with diverse origins, phenotypes, and functions. Activated CAFs secrete multiple factors that promote
[193] Conserved spatial subtypes and cellular neighborhoods of cancer ... — Cancer-associated fibroblasts (CAFs) are a multifaceted cell population essential for shaping the tumor microenvironment (TME) and influencing therapy responses. Characterizing the spatial organization and interactions of CAFs within complex tissue environments provides critical insights into tumor biology and immunobiology.
[197] The evolving tumor microenvironment: From cancer initiation to ... — PMID: 36917948 DOI: 10.1016/j.ccell.2023.02.016 Item in Clipboard Full text links Cite Display options Display options Format Abstract Cancers represent complex ecosystems comprising tumor cells and a multitude of non-cancerous cells, embedded in an altered extracellular matrix. The tumor microenvironment (TME) includes diverse immune cell types, cancer-associated fibroblasts, endothelial cells, pericytes, and various additional tissue-resident cell types. These host cells were once considered bystanders of tumorigenesis but are now known to play critical roles in the pathogenesis of cancer. Here, we review the importance of the TME in each stage of cancer progression, from tumor initiation, progression, invasion, and intravasation to metastatic dissemination and outgrowth. Understanding the complex interplay between tumor cell-intrinsic, cell-extrinsic, and systemic mediators of disease progression is critical for the rational development of effective anti-cancer treatments.
[219] Deciphering functional tumor-immune crosstalk through highly ... — The tumor microenvironment (TME) is a complex ecosystem where cancer cells dynamically interact with diverse non-malignant cells, including immune cells, fibroblasts, and endothelial cells, as well as the extracellular matrix. 1 These intricate interactions shape cancer progression and therapy response. 2 In particular, crosstalk between cancer cells and immune cells within the TME plays a
[220] Decoding the Complexity of Immune-Cancer Cell Interactions: Empowering ... — In this article, we provide an overview of why understanding the interactions between immune and tumor cells is so significant for developing anti-cancer therapeutics, particularly cancer immunotherapy. Understanding the intricate dynamics of cancer immunoediting and intercellular interactions between tumor and immune cells is crucial for the development of effective therapeutic approaches aimed at restoring immune control over tumors and achieving durable clinical responses. This approach enables the identification of the specific ligand–receptor pairs involved in immune cell interactions with cancer cells or the TME (Table 3). 23.Shelton S.E., Nguyen H.T., Barbie D.A., Kamm R.D. Engineering approaches for studying immune-tumor cell interactions and immunotherapy. 33.Ge Y., Chen L., Liu S., Zhao J., Zhang H., Chen P.R. Enzyme-Mediated Intercellular Proximity Labeling for Detecting Cell-Cell Interactions.
[221] A global database for modeling tumor-immune cell communication - Nature — The communications between tumor cells and 14 types of immune cells were characterized, and the involved ligand-receptor interactions were further integrated. 14190 human and 3650 mouse integrated
[223] Interactions between cancer cells and immune cells drive ... - PubMed — The mesenchymal subtype of glioblastoma is thought to be determined by both cancer cell-intrinsic alterations and extrinsic cellular interactions, but remains poorly understood. Here, we dissect glioblastoma-to-microenvironment interactions by single-cell RNA sequencing analysis of human tumors and …
[227] Sophisticated roles of tumor microenvironment in resistance to immune ... — The tumor microenvironment ... CAFs are the key components of the TME and exert pleiotropic functions to promote HCC development and therapeutic resistance. CAFs can facilitate cancer cells in acquiring malignant behaviors such as malignant proliferation, epithelial to mesenchymal transition (EMT), and cancer-stem-like properties, all of which
[228] Drug resistance and tumor immune microenvironment: An overview of ... — Key words: tumor immune microenvironment, drug resistance, cancer-associated fibroblasts, tumor-associated macrophages, extracellular matrix The immunosuppressive TME includes the immunosuppressive factors and cells, and physical and mechanical barriers, where impaired tumor antigen presentation process as well as metabolic alterations can be considered as the main site of drug resistance. Puttock et al (24) identified that the TAM population associated with cancer immunotherapy and ECM composition and found that tumor ECM can directly educate TAMs found in ovarian cancer tissues that are associated with a poor prognosis, and that targeting ECM can improve immune invasion and immunoth[...]e] [PubMed] [Google Scholar] Paclitaxel-loaded ginsenoside Rg3 liposomes for drug-resistant cancer therapy by dual targeting of the tumor microenvironment and cancer cells.
[229] The tumor microenvironment: a key player in multidrug resistance in ... — The tumor microenvironment: a key player in multidrug resistance in cancer - ScienceDirect The tumor microenvironment: a key player in multidrug resistance in cancer Author links open overlay panelLingnan Meng , Ying Zheng , Hao Liu , Daiming Fan The multidrug resistance (MDR) of cancer cells to various treatments remains a challenge. This review focuses on the role of the TME in promoting chemoresistance in tumor cells through the following mechanisms: (i) inhibiting the immune clearance of tumor cells and facilitating immune escape responses; (ii) stimulating the release of soluble paracrine factors to enhance tumor survival and growth; (iii) promoting survival and altering drug delivery through metabolic reprogramming; (iv) obstructing drug absorption by inducing changes in stomatal cells and blood vessels surrounding the tumor; and (v) inducing the cancer stem cell phenotype. For all open access content, the relevant licensing terms apply.
[230] The role of tumor microenvironment in drug resistance: emerging ... — CAFs' role in conferring drug resistance has been observed in different tumors (83-86) and can occur via the release of paracrine survival factors or by activating pathways in tumor cells that ultimately lead to decreased chemosensitivity, such as the expansion of therapy-resistant tumor-initiating cells and the enhanced expression of
[231] Immunosuppressive cells in cancer: mechanisms and potential therapeutic ... — Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets - PMC Immunosuppressive cells such as myeloid-derived suppressive cells, tumor-associated macrophages, tumor-associated neutrophils, regulatory T cells (Tregs), and tumor-associated dendritic cells are critical factors correlated with immune resistance. In addition, cytokines and factors secreted by tumor cells or these immunosuppressive cells also mediate the tumor progression and immune escape of cancers. Innate immune cells such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), tumor-associated dendritic cells (tDCs), and adoptive immune cells like the regulatory T cells (Tregs) are the main cellular components within the tumor microenvironment (TME). Thus, therapeutic strategies targeting these immunosuppressive cells include remodeling the TME and increasing the anti-tumor efficacy of immunotherapies. doi: 10.1016/j.cell.2021.05.027.
[232] Immunosuppressive cells in tumor immune escape and metastasis — Tumors develop numerous strategies to escape immune surveillance or metastasize: Tumors not only modulate the recruitment and expansion of immunosuppressive cell populations to develop the tumor microenvironment or pre-metastatic niche but also switch the phenotype and function of normal immune cells from a potentially tumor-reactive state to a
[233] Immunosuppressive cells in cancer: mechanisms and potential therapeutic ... — MDSC is the main type of immunosuppressive cell in cancer. Strategies targeting MDSCs to reverse the immunosuppression include depleting the populations of MDSCs by targeting VEGFR and CD33, blocking the migration and recruitment of MDSCs into TME by targeting the CCR2 or CXCR1/2, inhibiting the activity of MDSCs by targeting PGE2 and IDO
[234] Transforming cancer immunotherapy: Overcoming immunosuppression in ... — To enhance the immune system's antitumor response and transform an immune "cold" tumor into a "hot" tumor, current approaches primarily concentrate on three objectives: (1) boosting the immune system through adaptive T-cell therapy and vaccines for cancer , (2) reversing or blocking immunosuppressive factors through ICB therapy [4
[235] Reprogramming the Tumor Microenvironment to Improve Immunotherapy ... — In the following sections, we summarize approaches to reprogramming three different facets of the TME that promote immunosuppression—abnormal blood vessels, myeloid cells, and Tregs—and how these emerging strategies can be incorporated into clinical approaches to overcome microenvironment-driven resistance mechanisms to immunotherapy in patients.
[237] Tumor microenvironment complexity and therapeutic implications at a ... — Tumor microenvironment complexity and therapeutic implications at a glance | Cell Communication and Signaling | Full Text Search all BMC articles Tumor microenvironment complexity and therapeutic implications at a glance Tumor microenvironment complexity and therapeutic implications at a glance The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer.
[256] Therapeutic Targeting of Signaling Pathways Related to Cancer Stemness — To determine the efficacy of cancer treatment through the inhibition of the NF-κB pathway, various problems have been found: low efficacy of NF-κB inhibitors in addition to lymphoma and leukemia , immunosuppression after long-term systemic administration of these drugs and the appearance of short-term drug resistance (123, 124).
[257] Targeting cytokine and chemokine signaling pathways for cancer ... - PubMed — Targeting cytokine and chemokine signaling pathways for cancer therapy - PubMed Targeting cytokine and chemokine signaling pathways for cancer therapy Targeting cytokine and chemokine signaling pathways for cancer therapy The bottom left panel depicts the role of TGF-β in the tumor microenvironment (TME), highlighting its immunosuppressive effects that facilitate cancer immune escape by interacting with various immune cells such as Treg, MDSC, M1/M2 macrophages, DC, NK, and CTL. This normalization results in improved blood flow, reduced hypoxia, and increased immune infiltration, thereby potentially increasing T-cell activation, enhancing effector function, promoting tumor cell lysis by natural killer cells, and reducing PD-L1 expression on cancer cells, collectively creating an optimized microenvironment for the antitumor immune response.
[259] For and against tumor microenvironment: Nanoparticle-based strategies ... — For and against tumor microenvironment: Nanoparticle-based strategies for active cancer therapy - ScienceDirect Search ScienceDirect For and against tumor microenvironment: Nanoparticle-based strategies for active cancer therapy Open access Cancer treatment is challenged by the tumor microenvironment (TME), which promotes drug resistance and cancer cell growth. Additionally, nanoparticles can enhance immune responses by activating immune cells and reducing suppression within tumors. We also highlight novel strategies aimed at exploiting and overcoming the TME, leveraging nanoparticle-based approaches for targeted cancer therapy through precise TME modulation. Recommended articles No data was used for the research described in the article. © 2025 Published by Elsevier Ltd. Recommended articles No articles found. Cookies are used by this site. For all open access content, the relevant licensing terms apply.
[274] Tumor Microenvironment: From 2D Cultures to Organ-on-a-Chip ... — Tumor-on-a-chip technology offers a transformative approach by accurately replicating the tumor microenvironment and predicting physiological responses to anti-cancer therapies. As a result, it is becoming an essential translational tool for improving cancer research and drug development. Future directions and considerations
[276] Stromal reprogramming: A target for tumor therapy — Therapy can be directed for targeting signaling related to stromal reprogramming. TGF-β is a pleotropic, immunosuppressive cytokine deregulated in many tumors, and it acts on a variety of TME cells including CAFs. TGF-β is a strong inducer of stromal reprogramming and heterogeneity, so it can be a promising target .
[280] The Crosstalk Between Tumor Cells and the Immune Microenvironment in ... — The complex interplay between cancer and the immune TME influences the outcome of immunotherapy and of many other anti-cancer therapies. Herein, we present an updated view of the pro- and anti-tumor activities of the main immune cell populations present in breast TME, such as T and NK cells, myeloid cells, innate lymphoid cells, mast cells and
[281] Epigenetic interplay between immune, stromal and cancer cells in the ... — In the tumor microenvironment, tumor-infiltrating immune cells play a crucial role inducing epigenetic alterations in both stroma and tumor cells which finally will impact the outcome of the disease. In fact, several studies have shown that chronic inflammation increases the risk of cancer and promotes tumor progression [ 43 , 44 ].
[282] Immunometabolic Interplay in the Tumor Microenvironment - Cell Press — Immune cells' metabolism influences their differentiation and function. Given that a complex interplay of environmental factors within the tumor microenvironment (TME) can have a profound impact on the metabolic activities of immune, stromal, and tumor cell types, there is emerging interest to advance understanding of these diverse metabolic phenotypes in the TME.
[286] The updated landscape of tumor microenvironment and drug repurposing — Advertisement The updated landscape of tumor microenvironment and drug repurposing Signal Transduction and Targeted Therapy volume 5, Article number: 166 (2020) Cite this article 46k Accesses 450 Citations 29 Altmetric Metrics details Subjects Abstract Accumulating evidence shows that cellular and acellular components in tumor microenvironment (TME) can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Cancer research and treatment have switched from a cancer-centric model to a TME-centric one, considering the increasing significance of TME in cancer biology. Herein, we present an updated image of TME with emphasis on hypoxic niche, immune microenvironment, metabolism microenvironment, acidic niche, innervated niche, and mechanical microenvironment. This review depicts a comprehensive and vivid landscape of TME from biology to treatment.
[290] Therapeutic Targeting of the Tumor Microenvironment - PubMed — Therapeutic Targeting of the Tumor Microenvironment - PubMed Search: Search Your saved search Name of saved search: Strategies to therapeutically target the tumor microenvironment (TME) have emerged as a promising approach for cancer treatment in recent years due to the critical roles of the TME in regulating tumor progression and modulating response to standard-of-care therapies. Here, we summarize the current knowledge regarding the most advanced TME-directed therapies, which have either been clinically approved or are currently being evaluated in trials, including immunotherapies, antiangiogenic drugs, and treatments directed against cancer-associated fibroblasts and the extracellular matrix. Targeting the tumor microenvironment: Potential strategy for cancer therapeutics. The tumor microenvironment as driver of stemness and therapeutic resistance in breast cancer: New challenges and therapeutic opportunities. Unlocking the potential of the tumor microenvironment for cancer therapy.
[291] The tumor microenvironment is an ecosystem sustained by ... - Cell Press — Interactions between cancer cells, CAFs, immune cells, and other stromal cells all contribute to the overall phenotype of a tumor. In order to effectively target tumors, the tumor ecosystem as a whole must therefore be considered, as therapeutic agents will also act on other cells in the TME and on the ways in which they interact with each other.
[292] Tumor microenvironment complexity and therapeutic implications at a ... — Tumor microenvironment complexity and therapeutic implications at a glance | Cell Communication and Signaling | Full Text Search all BMC articles Tumor microenvironment complexity and therapeutic implications at a glance Tumor microenvironment complexity and therapeutic implications at a glance The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer.
[293] Tumor microenvironment as a therapeutic target in cancer - PMC — Tumor microenvironment as a therapeutic target in cancer - PMC There is a significant therapeutic advantage in targeting the TME compared with directly targeting cancer cells, because cancer cells are prone to drug resistance due to their genomic instability, whereas non-tumor cells in the TME have a genetically more stable nature and are more vulnerable. For example, fibroblast activation protein (FAP)-positive CAFs secrete CXCL12, which protected PDAC cancer cells from anti-tumor T-cells and caused unresponsiveness to immune checkpoint blockade (ICB) therapies in mouse PDAC models30. Cancer Cell 28, 831–833, doi: 10.1016/j.ccell.2015.11.002 (2015). Cancer Cell 25, 735–747, doi: 10.1016/j.ccr.2014.04.021 (2014). Cancer Cell 16, 173–174, doi: 10.1016/j.ccr.2009.08.014 (2009). Cancer Cell 32, 42–56 e46, doi: 10.1016/j.ccell.2017.06.003 (2017).
[307] The tumor microenvironment: Current Biology - Cell Press — Immune cells are critical components of the tumor microenvironment. Depending on the context, a dichotomy exists in the relationship between immune cells and the tumor microenvironment: immune cells can either suppress tumor growth or promote it ().Persistent inflammation due to chronic infection is a common mechanism underlying tumor formation in several types of cancer, including colorectal
[308] Cellular and Extracellular Components in Tumor Microenvironment and ... — During the cancer development, myeloid-derived suppressor cells (MDSCs), including macrophages, dendritic cells (DCs), and myeloid precursors, play a role in promoting tumor progression and angiogenesis, via suppressing T cells and NK cells by producing cytokines such as IL-6, IL-10, and TGF-β and also differentiating into TAMs under hypoxic conditions . Tumor blood vessels in TME provide fresh oxygen and nutrition support for tumor tissues and help cancer cells move into the blood stream and spread to distant sites (Table 1). EVs have emerged as critical mediators of the distant communication between the tumor and the TME cells by carrying multiple biologically active molecules, which can promote cancer initiation and progression . A. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cancer-associated fibroblasts regulate tumor-initiating cell plasticity in hepatocellular carcinoma through c-Met/FRA1/HEY1 signaling.