EEPD1 Inhibition Unleashes Antitumor Immunity in Colorectal Cancer by Activating the cGAS‐STING Pathway

ABSTRACT The efficacy of immunotherapy in colorectal cancer (CRC) is frequently limited by an immunosuppressive tumor microenvironment. Here, we identify exonuclease/endonuclease/phosphatase domain‐containing protein 1 (EEPD1), a gatekeeper of homologous recombination (HR) repair, as a key driver of this immune exclusion. Downregulation of EEPD1 profoundly compromises HR in CRC cells, which curtails their proliferative and metastatic capacities in vitro and in vivo. Mechanistically, EEPD1 deficiency fuels genomic instability, leading to cytosolic DNA accumulation and activation of the cGAS‐STING‐type I interferon axis. This cascade promotes dendritic cell maturation, skews macrophages toward a proinflammatory M1 phenotype, and enhances tumor‐associated antigen presentation, culminating in robust CD8 + T cell activation and cytotoxicity. Our findings elucidate a direct mechanism by which targeting EEPD1 sensitizes CRC to anti‐PD1 immunotherapy. Our work establishes EEPD1 as a promising therapeutic target to overcome immune checkpoint blockade resistance in colorectal cancer.