CCL3 promotes oxaliplatin resistance in gastric cancer via CCR5-mediated tumor cell survival and macrophage M2 polarization.

Although oxaliplatin (Oxa)-based chemotherapy is a standard treatment for gastric cancer (GC), its clinical efficacy is frequently limited by the development of Oxa resistance. Chemokine CCL3 is linked to tumor growth, which can result in tumor-immune interactions and treatment resistance. This work examined the function of CCL3 in Oxa resistance in macrophages, patient-derived organoids (PDO), and GC cells. Differential expression, weighted gene co-expression network analysis (WGCNA), PPI network, and ROC analysis were performed on the GSE128967 dataset. Oxa-resistant GC cell lines (MKN45/Oxa, SGC7901/Oxa) and PDOs were used to evaluate the function of CCL3 by siRNA knockdown and overexpression. To evaluate CCL3-driven macrophage polarization and its effect on Oxa sensitivity, THP-1-derived macrophages were co-cultured with GC cells. Cell viability, migration/invasion, and expression of CCL3, CCR1/CCR5, and M1/M2 markers were examined by Transwell assays, qRT-PCR, CCK-8, and Western blot. WGCNA highlighted an FOLFOX-related yellow module, from which CCL3 emerged as a hub gene with the highest prognostic accuracy. CCL3 was upregulated in Oxa-resistant GC cells and PDOs. CCL3 knockdown reduced cell migration, invasion, and PDO formation under Oxa treatment, whereas overexpression enhanced resistance. CCL3-overexpressing GC cells promoted M2 polarization of co-cultured macrophages, which in turn further increased Oxa resistance in GC cells. Mechanistically, CCR5 mediated CCL3-induced chemoresistance and macrophage M2 polarization. The CCL3/CCR5 axis drives Oxa resistance in GC by boosting tumor cell survival and fostering immunosuppressive M2 macrophages. Targeting this pathway may offer a strategy to overcome chemoresistance in GC.