Personalized Autologous Vaccines Activate Stimulator of Interferon Gene and Suppress Dendritic Cell Programmed Death Ligand 1 to Potentiate Antitumor Immunity.

Abstract

Cancer vaccines have underperformed clinically, largely because antigen-specific CTL priming and expansion are constrained by insufficient costimulatory activation and increased DC-mediated coinhibition. Here, we present a personalized cancer vaccine platform, STAR, which engineers stimulator of interferon gene (STING)-activating autologous tumor-derived microvesicles (TMVs) to concurrently amplify costimulatory signaling and relieve DC coinhibition during antigen cross-presentation. TMVs provide broad tumor antigen cargo and intrinsic STING activity; loading manganese phosphate nanoparticles (MnPs) potentiates cGAS-STING signaling, drives DC maturation, and enhances antigen cross-presentation. Importantly, concurrent delivery of PD-L1-targeting siRNA (siPD-L1) effectively inhibits DC-associated PD-L1, freeing CD80 to engage CD28 and limiting PD-1/PD-L1 signaling and thereby significantly enhancing antigen-specific CD8⁺ T cells. In mouse models, STAR vaccination elicited durable prophylactic immunity and achieved substantial therapeutic efficacy against melanoma and colorectal tumors without additional immunotherapies. Notably, patient-specific STAR vaccines derived from surgically resected tumors effectively prevented postoperative recurrence and metastasis in aggressive melanoma and triple-negative breast cancer models, thereby highlighting their translational potential. Overall, the STAR vaccine platform offers a versatile and clinically applicable approach to enhancing personalized cancer immunotherapy across diverse cancer types.