Thermosensitive Hydrogel In Situ Vaccine for Lymph Node Targeting and Enhanced Immunotherapy

Abstract In situ vaccination is a promising strategy for cancer immunotherapy that enables the convenient induction of diverse tumor antigens directly within a host. However, the immunosuppressive tumor microenvironment markedly impairs the antigen‐presenting capacity of dendritic cells (DCs), resulting in the inefficient presentation of locally generated antigens and, consequently, suboptimal immune responses. To address this challenge, a localized in situ vaccine platform (Gel/MTO&Snp) designed is developed to actively transport tumor‐derived antigens to tumor‐draining lymph nodes (tDLNs), thereby eliciting potent antitumor immunity. Gel/MTO&Snp consists of a thermosensitive hydrogel incorporating subsized PEI/CpG nanocomposite particles (Snp, ≈10 nm) and chemotherapeutic agent mitoxantrone (MTO). Upon near‐infrared (NIR) laser irradiation, Gel/MTO&Snp simultaneously achieved photothermal and chemotherapeutic effects following local injection, thereby inducing immunogenic cell death and triggering antigen release at tumor sites. These liberated antigens are subsequently adsorbed onto positively charged Snp particles and transported via lymphatic vessels to tDLNs in a size‐dependent manner, where they enhanced antigen presentation and immune activation. This targeted antigen delivery markedly promotes DC maturation and effectively stimulates systemic anticancer immunity, providing a novel strategy to optimize the efficacy of in situ cancer vaccines.