Objective To elucidate the role of C-C motif receptor 5 (CCR5)⁺tumor-associated macrophages (TAMs) in the immune regulation of gastric cancer.

Methods This study integrated four independent cohorts, including three groups of gastric cancer patients from Zhongshan Hospital, Fudan University (448 cases in the radical surgery cohort, 33 cases in the neoadjuvant immunotherapy cohort, and 46 cases in the palliative immunotherapy cohort) and one group of 336 patients from The Cancer Genome Atlas (TCGA) of the gastric cancer database. The infiltration degree of CCR5⁺ TAMs in tumor tissues was determined by immunofluorescence, and the correlation with clinical outcomes was analyzed. The phenotype of CCR5⁺ TAMs was detected by flow cytometry analysis, and an in vitro fresh tumor tissue culture system was used to evaluate the potential therapeutic effect of blocking CCR5 in gastric cancer.

Results High infiltration of CCR5⁺TAMs was significantly associated with adverse clinical outcomes and tumor progression in patients with resectable gastric cancer. In immune therapy cohort, the infiltration degree of CCR5⁺TAMs was negatively correlated with the objective response rate of patients treated with immune checkpoint inhibitors. CCR5⁺TAMs were found to induce CD8⁺T cell exhaustion through the expression of immunosuppressive molecules, including PD-L1 and IL-10. Therapy targeting CCR5 (especially in tumors with high infiltration of CCR5⁺TAMs) effectively reversed the immunosuppressive tumor microenvironment.

Conclusions CCR5⁺TAMs infiltration serves as an independent prognostic factor for patients with gastric cancer. These cells contribute to immune evasion via the expression of PD-L1 and IL-10, leading to CD8⁺T cell dysfunction. The study suggests that anti-CCR5 therapies could potentiate antitumor immunity, thereby offering a potential novel therapeutic strategy for gastric cancer.