CCL26–CX3CR1 Axis Mediates a Feedback Loop between Cancer Cell and PMN-MDSCs to Promote CD8 ⁺ T Cell Exhaustion during Stomach Carcinogenesis

The development of an immunosuppressive microenvironment is a critical factor in stomach carcinogenesis. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) serve a pivotal function in mediating immune suppression. However, the precise mechanisms underlying PMN-MDSCs infiltration into the tumor immune microenvironment (TIME) and their immunosuppressive functions remain poorly understood. In this investigation, we observed that PMN-MDSCs were up-regulated during stomach carcinogenesis, with gastric cancer (GC) cells secreting CCL26 to promote the infiltration of PMN-MDSCs into the TIME via the CX3CR1 receptor. The infiltrating CX3CR1⁺ PMN-MDSCs secreted transforming growth factor-β1 (TGF-β1), which, through the SMAD2/3/SNAI1 signaling pathway, further sustained the secretion of CCL26 by GC cells, establishing a positive feedback loop. Additionally, CX3CR1⁺ PMN-MDSCs suppressed mTOR signaling via TGF-β1 and competed with CD8⁺ T cells for glucose, disrupting glycolysis and leading to T cell exhaustion. Notably, inhibition of CX3CR1 reduced the infiltration of PMN-MDSCs, improved anti-PD-1 therapeutic efficacy, and suppressed tumor growth. In conclusions, this study illustrated that the CCL26-CX3CR1 axis mediates a positive feedback loop between GC cells and PMN-MDSCs, promoting CD8⁺ T cell exhaustion and tumorigenesis. Targeting CX3CR1 on PMN-MDSCs could serve as a potential therapeutic strategy to prevent stomach carcinogenesis.