Programmed death receptor-1 (PD-1) inhibitors are ineffective against microsatellite-stable (MSS) colorectal cancer. Electroacupuncture (EA) has oncosuppressive and immunomodulatory properties. Here, we investigated the antitumor effects of EA and explored the feasibility of EA combined with anti-PD-1 in MSS colorectal cancer. Results showed that EA exerted its antitumor effect in an intensity-specific manner, and moderate-intensity EA (1.0 mA) induced maximal tumor inhibition. EA enhanced antitumor immune responses by increasing lymphocytes and granzyme B (GzmB) levels, as well as activating the stimulator of IFN genes (STING) pathway. EA combined with anti-PD-1 showed superior efficacy compared with either monotherapy in multiple MSS colorectal cancer mouse models. Single-cell RNA sequencing revealed that cotreatment reprogrammed the tumor immune microenvironment (TIME), as characterized by enhancement of cytotoxic functions. Mechanically, we found that the potentiated effect of EA was dependent upon the STING pathway. Collectively, EA reshapes the TIME of MSS colorectal cancer and sensitizes tumors to anti-PD-1 in a STING pathway-dependent manner. These results provide a mechanistic rationale for using EA as an immunomodulatory strategy to improve the clinical efficacy of anti-PD-1 in MSS colorectal cancer. EA is safe, well-tolerated, and feasible for clinical translation as a promising strategy for treating MSS colorectal cancer.
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