A Versatile Polymer‐Based In Situ Nanovaccine to Boost Cancer Immunotherapy

ABSTRACT In situ vaccination is a promising strategy for personalized cancer immunotherapy; however, its efficacy is often limited by rapid antigen degradation, inefficient delivery to lymph nodes (LNs), and the immunosuppressive tumor microenvironment (TME). To overcome these challenges, we developed a versatile in situ cancer nanovaccine by conjugating the TLR7/8 agonist R848 to a polymeric immunogenic cell death (ICD) inducer, termed G4P‐C7A‐R848. In aqueous solution, G4P‐C7A‐R848 self‐assembles into nanoparticles (PCR‐NPs), which accumulate at tumor sites following systemic administration. Within tumors, PCR‐NPs trigger the release of tumor‐associated antigens from tumor cells via ICD and subsequently capture them to form an in situ nanovaccine. These nanovaccines then traffic to tumor‐draining LNs (TDLNs), where they promote dendritic cell maturation and T cell activation. Moreover, the nanovaccine reprograms macrophages toward the tumoricidal M1 phenotype, thereby alleviating immunosuppression in the TME. This coordinated action enhances the infiltration and activation of CD8+ T cells, leading to robust and durable antitumor immunity. Across multiple murine tumor models, PCR‐NPs treatment resulted in significant tumor regression and prolonged survival. This study offers a simple yet effective platform for developing potent in situ cancer vaccines.