Binary Cooperative Prodrug Nanoparticles Improve Immunotherapy by Synergistically Modulating Immune Tumor Microenvironment

TLDR

Checkpoint blockade immunotherapy shows promise for many cancers but is limited by low response rates due to insufficient tumor immunogenicity and an immunosuppressive tumor microenvironment. This study designs a tumor‑microenvironment‑activatable binary cooperative prodrug nanoparticle (BCPN) to enhance immunotherapy by synergistically modulating the immune tumor microenvironment. BCPN combines a tumor‑acidity and reduction‑responsive oxaliplatin prodrug that induces immunogenic cell death with a reduction‑activatable NLG919 homodimer that inhibits IDO‑1, and its PEG shell cleaves in acidic tumors to switch from negative to positive charge, improving accumulation, penetration, and activation by glutathione. In mouse models of breast and colorectal cancer, activated BCPN increased cytotoxic T‑cell infiltration, suppressed IDO‑1 and regulatory T cells, and achieved superior tumor regression and metastasis prevention compared to free oxaliplatin or the oxaliplatin–NLG919 combination.

Abstract

Checkpoint blockade immunotherapy is promising for clinical treatment of various malignant tumors. However, checkpoint blockade immunotherapy suffers from a low response rate due to insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment (ITM). In this study, a tumor-microenvironment-activatable binary cooperative prodrug nanoparticle (BCPN) is rationally designed to improve immunotherapy by synergistically modulating the immune tumor microenvironment. BCPN is purely constructed from a tumor acidity and reduction dual-responsive oxaliplatin (OXA) prodrug for triggering immunogenic cell death (ICD) and eliciting antitumor immunity, and a reduction-activatable homodimer of NLG919 for inactivating indoleamine 2,3-dioxygenase 1, which is a key regulator for ITM. Upon tumor-acidity-triggered cleavage of the poly(ethylene glycol) shell, PN shows negative to positive charge switch for enhanced tumor accumulation and deep penetration. OXA and NLG919 are then activated in the tumor cells via glutathione-mediated reduction. It is demonstrate that activated OXA promotes intratumoral accumulation of cytotoxic T lymphocytes by triggering ICD of cancer cells. Meanwhile, NLG919 downregulates IDO-1-mediated immunosuppression and suppresses regulatory T cells. Most importantly, PN shows much higher efficiency than free OXA or the combination of free OXA and NLG919 to regress tumor growth and prevent metastasis of mouse models of both breast and colorectal cancer.