Inhibiting CXCL12/CXCR4 axis enhances T cell activity in gastric cancer

This study aimed to investigate how the CXCL12/CXCR4 axis facilitates immune evasion in gastric cancer (GC) by enhancing cellular communication between cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) using single-cell transcriptome sequencing. Single-cell RNA sequencing of tumor and normal gastric tissues in a murine GC model revealed an increased macrophage population in GC, characterized by predominantly M2-polarized TAMs. The study identified that the CXCL12/CXCR4 axis potentially triggers M2 macrophage polarization through mediating communication between CAFs and TAMs. In vitro experiments confirmed that CAFs induced M2 polarization through CXCL12/CXCR4 signaling. Inhibition of the PD-L1/PD-1 axis disrupted communication between M2 macrophages and T cells, which enhanced T cell activation. In vivo experiments showed that silencing CXCR4 reduced M2 macrophages and PD-L1 expression, leading to improved T cell proliferation, reduced immune evasion, and slower tumor growth. These findings highlight the role of the CXCL12/CXCR4 axis in driving immune evasion in GC by inducing M2 polarization and PD-L1-mediated T cell suppression, and indicate a promising therapeutic target for GC immunotherapy. Schematic Molecular Mechanism Illustrating CXCL12/CXCR4 Axis-Mediated Cellular Communication between CAFs and TAMs Promoting Gastric Cancer Immune Evasion.