GPR183 senses 7α,25-OHC to drive T _reg differentiation and tumor immune evasion via AXL-JAK2-STAT5 signaling

Regulatory T cell (T _reg ) accumulation within the tumor microenvironment is a major contributor to immune evasion and immunotherapy resistance. However, the metabolic signals orchestrating T _reg lineage commitment remain poorly defined. We identify that the oxysterol 7α,25-dihydroxycholesterol (7α,25-OHC), produced by Vimentin ⁺ stromal cells, acts through GPR183 to promote T _reg differentiation and suppressive identity. In patients with gastric cancer (GC), GPR183 ⁺ T _reg infiltration correlates with advanced disease and poor survival. In syngeneic tumor models, conditional GPR183 deletion, specifically in CD4 ⁺ T cells or T _reg cells, demonstrates its cell-intrinsic requirement for high-cholesterol-diet–induced T _reg expansion and tumor growth, thereby abrogating immune evasion and restoring CD8 ⁺ T cell effector function. Mechanistically, 7α,25-OHC–GPR183 signaling activates the AXL-JAK2-STAT5 pathway to reinforce Foxp3 expression. Last, GPR183 antagonism modestly enhances anti-PD-1 efficacy in a model-dependent manner and prevents therapy-induced T _reg expansion. These findings identify the 7α,25-OHC–GPR183–AXL axis as a potential metabolic checkpoint linking cholesterol metabolism to immune suppression, suggesting a potential therapeutic strategy to enhance antitumor immunity.