A manganese-based nanoplatform leveraging chemodynamic and adjuvant effects for in situ vaccination against colorectal cancer

Abstract

In situ tumor vaccination activates host immunity through endogenous tumor-associated antigens (TAAs) and represents a promising strategy for tumor immunotherapy. However, insufficient immunogenicity and an immunosuppressive tumor microenvironment have limited the efficacy of in situ tumor vaccination in colorectal cancer (CRC). Here, we presented a versatile manganese-based nanoplatform (MnP@LNP) for chemodynamic therapy and in situ tumor vaccination to enable CRC immunotherapy. Upon encountering the acidic tumor microenvironment, MnP@LNPs underwent continuous release of Mn2+ accompanied by the generation of highly destructive hydroxyl radicals. When administered rectally to the primary tumor site, MnP@LNPs alone achieved 71.0% inhibition of primary tumors, while their combination with αPD-L1 increased the inhibition rate to 83.8% and concurrently suppressed distant tumors by 81.9%. The primary function of MnP@LNPs was to generate an in situ vaccine by inducing immunogenic cell death of tumor cells. The released TAAs, together with Mn2+ as an adjuvant, activated the cGAS-STING signaling pathway, driving a systemic cytotoxic T-lymphocyte response against metastatic tumors. Besides, this therapeutic strategy also reprogrammed the intestinal milieu by enriching beneficial microbial populations (e.g., Alistipes and Dubosiella) and upregulating the levels of immunostimulatory metabolites, such as indole-3-aldehyde and indole-3-lactic acid. Collectively, MnP@LNPs serve as a nanotherapeutic that orchestrates local-to-systemic antitumor immunity while fostering an immune-favorable intestinal ecosystem, representing a promising platform for CRC immunotherapy.