Combination anti-PD-1 and electroacupuncture induces a potent anti-tumor immune response in microsatellite-stable colorectal cancer.

Programmed death receptor-1 (PD-1) inhibitors are ineffective against microsatellite-stable (MSS) colorectal cancer (CRC). Electroacupuncture (EA) has onco-suppressive and immunomodulatory properties. Here, we investigated the anti-tumor effects of EA and explored the feasibility of EA combined with anti-PD-1 in MSS CRC. Results showed that EA exerted its anti-tumor effect in an intensity-specific manner, and moderate-intensity EA (1.0 mA) induced maximal tumor inhibition. EA enhanced anti-tumor immune responses by increasing lymphocytes and granzyme B (GzmB) levels, as well as activating the stimulator of interferon genes (STING) pathway. EA combined with anti-PD-1 showed superior efficacy compared with either monotherapy in multiple MSS CRC 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 the potentiated effect of EA was dependent upon the STING pathway. Collectively, EA reshapes the TIME of MSS CRC 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 CRC. EA is safe, well-tolerated, and feasible for clinical translation as a promising strategy for treating MSS CRC.