CCL8-dependent recruitment of natural killer cells enhances the antitumor activity of neoadjuvant chemotherapy in gastric cancer

Neoadjuvant chemotherapy (NACT) has become a standard treatment for patients with locally advanced gastric cancer (GC), yet the effects of NACT on natural killer (NK) cells remain insufficiently characterized. In this study, we investigated the immune remodeling induced by NACT in paired tumor samples from GC patients and in a murine model, aiming to uncover mechanisms that could guide combination strategies with immunotherapy. We observed enhanced infiltration of antitumor immune cells, particularly CD8⁺ T cells and NK cells, after NACT in both human and mouse tumors, with elevated levels of these cells correlating with improved clinical responses. In vivo depletion experiments confirmed that NK cells contributed to the antitumor efficacy of NACT. In vitro, NACT-treated tumor cells displayed enhanced chemotactic effects on NK92 cells. Mechanistically, NACT activated the mitogen-activated protein kinase (MAPK) pathway in GC cells, inducing CCL8 secretion and facilitating NK cell recruitment. Notably, in an advanced GC patient, the combination of NACT and adoptive NK cell transfer resulted in increased peripheral NK cell counts and a favorable clinical response. Together, these findings reveal that NACT stimulates NK cell recruitment through tumor-derived CCL8 via MAPK activation and support a promising therapeutic rationale for combining NACT with NK cell-based immunotherapy in GC.