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Peer-reviewedCC BYScience Advances

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

  • Yang Qu1,2,3
  • Yihan Xu1,2,3
  • Jingchao Bai1,2,3,4
  • Yuhan Zhang1,2,3,5
  • Ning Ji1,2,3
  • Xinxin Li1,2,3
  • Hui Li1,2,3
5 affiliations
  1. 1Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
  2. 2Tianjin Key Laboratory of Digestive Cancer, Tianjin Clinical Research Center for Cancer, Tianjin, China.
  3. 3National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
  4. 4Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
  5. 5Department of Radiation Oncology, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
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Abstract

Regulatory T cell (Treg) accumulation within the tumor microenvironment is a major contributor to immune evasion and immunotherapy resistance. However, the metabolic signals orchestrating Treg 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 Treg differentiation and suppressive identity. In patients with gastric cancer (GC), GPR183⁺ Treg infiltration correlates with advanced disease and poor survival. In syngeneic tumor models, conditional GPR183 deletion, specifically in CD4⁺ T cells or Treg cells, demonstrates its cell-intrinsic requirement for high-cholesterol-diet-induced Treg 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 Treg 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.

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Cite

BibTeXRIS
BibTeX
@article{qu2026gpr183,
  title = {{GPR183 senses 7α,25-OHC to drive Treg differentiation and tumor immune evasion via AXL-JAK2-STAT5 signaling}},
  author = {Yang Qu and Yihan Xu and Jingchao Bai and Yuhan Zhang and Ning Ji and Xinxin Li and Hui Li},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeh9736},
  url = {https://www.science.org/doi/abs/10.1126/sciadv.aeh9736},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - GPR183 senses 7α,25-OHC to drive Treg differentiation and tumor immune evasion via AXL-JAK2-STAT5 signaling
AU  - Yang Qu
AU  - Yihan Xu
AU  - Jingchao Bai
AU  - Yuhan Zhang
AU  - Ning Ji
AU  - Xinxin Li
AU  - Hui Li
PY  - 2026
DA  - 2026/10/30
JO  - Science Advances
DO  - 10.1126/sciadv.aeh9736
UR  - https://www.science.org/doi/abs/10.1126/sciadv.aeh9736
AB  - Regulatory T cell (Treg) accumulation within the tumor microenvironment is a major contributor to immune evasion and immunotherapy resistance. However, the metabolic signals orchestrating Treg 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 Treg differentiation and suppressive identity. In patients with gastric cancer (GC), GPR183⁺ Treg infiltration correlates with advanced disease and poor survival. In syngeneic tumor models, conditional GPR183 deletion, specifically in CD4⁺ T cells or Treg cells, demonstrates its cell-intrinsic requirement for high-cholesterol-diet-induced Treg 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 Treg 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.
SN  - 2375-2548
ER  -