Cancer vaccines have shown tremendous potential in preventing and treating cancer by providing immunogenic antigens to initiate specific tumor immune responses. An in situ vaccine prepared from an autologous tumor can mobilize a patient's own tumor cell lysate as a reservoir of specific antigens, thus triggering a broad immune response and diverse antitumor immunity in an individually tailored manner. Its efficacy is much better than that of conventional vaccines with a limited number of epitopes. Several conventional therapies, including radiotherapy (RT), chemotherapeutics, photodynamic therapy (PDT), and photothermal therapy (PTT) can activate an anticancer in situ vaccine response by inducing immunogenic cell death (ICD), triggering the exposure of tumor-associated antigens (TAAs), cancerous testis antigens, neoantigens, and danger-associated molecular patterns (DAMPs) with low cost. However, the immunogenicity of dying tumor cells is low, making released antigens and DAMPs insufficient to initiate a robust immune response against malignant cancer. Moreover, the immunosuppressive tumor microenvironment (TME) severely hinders the infiltration and sensitization of effector immune cells, causing tolerogenic immunological effects.Herein, we mainly focus on the research in developing nanoplatforms to surmount the major challenges met by ICD-based in situ vaccines. We first summarized a variety of nanotechnologies that enable enhanced immunogenicity of dying cancer cells by enhancing antigenicity and adjuvanticity. The robust antigenicity was obtained via regulating the tumor cells death mode or the dying state to amplify the recognition of tumor debris by professional antigen-presenting cells (APCs). The adjuvanticity was potentiated by raising the level or intensifying the activity of endogenous adjuvants or promoting the intelligent delivery of exogenous immunostimulants to activate immune cell recruitment and promote antigen presentation. Additionally, versatile approaches to reverse immunosuppressive TME to boost the in situ tumor vaccination response are also highlighted in detail. On one hand, by modulating the cell metabolism in TME, the expansion and activity of effector versus immunosuppressive cells can be optimized to improve the efficiency of in situ vaccines. On the other hand, regulating cellular components in TME, such as reversing adverse immune cell phenotypes or inhibiting the activity of interstitial cells, can also significantly enhance the ICD-based antitumor immunotherapy effect. Finally, our viewpoint on the future challenges and opportunities in this hopeful area is presented. We expect that this Account can offer much more insight into the design, planning, and development of cutting-edge in situ tumor vaccine platforms, promoting more attention and academic-industry collaborations, accelerating the advanced progress of in situ tumor vaccine-based immunotherapy in the clinic.

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