Abstract

Inadequate antigen presentation, driven by epigenetic repression of major histocompatibility complex class I (MHC-I), represents a fundamental barrier to effective cancer immunotherapy.. Here, we identify polycomb group ring finger 1 (PCGF1) as a tumor cell–intrinsic epigenetic repressor of MHC-I through a genome-wide CRISPR screen. Genetic ablation of PCGF1 alone is sufficient to relieve repressive histone modifications (H2AK119ub and H3K27me3) at both the MHC-I gene cluster and its master regulator NLRC5, thereby restoring cell-surface antigen presentation and immunotherapy sensitivity. Building on this epigenetic foundation, we introduce modular engineering strategies to enhance translational robustness against tumor antigen heterogeneity. Specifically, CRISPR activation (CRISPRa) is used to broaden the repertoire of endogenous tumor antigens without altering the restored antigen presentation machinery. These epigenetically reprogrammed cells are subsequently cryoinactivated and formulated into an injectable thermosensitive chitosan-based hydrogel, in which manganese-mediated STING activation serves as an immunostimulatory adjuvant to amplify antigen capture and systemic T-cell priming.Collectively, this study establishes epigenetic reprogramming of antigen presentation as a foundational principle for whole-cell vaccine design and demonstrates how modular antigen and innate immune augmentation can enhance therapeutic robustness without obscuring the core mechanism. This platform offers a rational and adaptable framework for overcoming immune resistance in next-generation cancer immunotherapy.