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<p>Gastric cancer (GC) derives limited benefit from immune checkpoint blockade (ICB), in part due to stromal-mediated immune suppression. To investigate the underlying mechanisms, we performed single-cell RNA sequencing on 14 GC specimens from patients treated with neoadjuvant ICB. We identified a distinct subset of TRPA1+ cancer-associated fibroblasts (CAFs) maintained by tumor-derived midkine (MDK) through LEF1-dependent transcription under ICB pressure. These TRPA1+ CAFs drive immunosuppression by secreting WNT5A, which polarizes SPP1+ macrophages and subsequently promotes the accumulation of CD25 + FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment. Disrupting this stromal-myeloid-lymphoid axis via WNT5A inhibition or SPP1+ macrophage depletion reduced Treg infiltration and enhanced the antitumor efficacy of anti-PD-L1 therapy in vivo. Our study unveils an MDK-TRPA1 + CAF-mediated mechanism of ICB resistance in GC and highlights the WNT5A-SPP1+ macrophage pathway as a promising target to overcome immunotherapy resistance.</p>

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Midkine-activated TRPA1+ cancer-associated fibroblasts promote immunotherapy resistance in gastric cancer through a WNT5A-mediated treg circuit

  • 期刊论文

  • 发表日期：

    2026年8月3日

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  • Hualong Zheng,
  • Xiaoqian Ye,
  • Linyong Zheng,
  • Xiaobo Huang,
  • Haidan Yan,
  • Zhilong Lin,
  • Qing Zhong,
  • Ruhong Tu,
  • Zhiquan Zhang,
  • Youxin Gao,
  • Qiang Huang,
  • Yifan Li,
  • Yi Li,
  • Xinpeng Yang,
  • Chenyang Jiang,
  • Xiaojing Guo,
  • Maosen Wang,
  • Chaohui Zheng,
  • Ping Li,
  • Jiabin Wang,
  • Jianxian Lin,
  • Changming Huang,
  • Qiyue Chen,
  • Jianwei Xie

摘要

Gastric cancer (GC) derives limited benefit from immune checkpoint blockade (ICB), in part due to stromal-mediated immune suppression. To investigate the underlying mechanisms, we performed single-cell RNA sequencing on 14 GC specimens from patients treated with neoadjuvant ICB. We identified a distinct subset of TRPA1+ cancer-associated fibroblasts (CAFs) maintained by tumor-derived midkine (MDK) through LEF1-dependent transcription under ICB pressure. These TRPA1+ CAFs drive immunosuppression by secreting WNT5A, which polarizes SPP1+ macrophages and subsequently promotes the accumulation of CD25 + FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment. Disrupting this stromal-myeloid-lymphoid axis via WNT5A inhibition or SPP1+ macrophage depletion reduced Treg infiltration and enhanced the antitumor efficacy of anti-PD-L1 therapy in vivo. Our study unveils an MDK-TRPA1 + CAF-mediated mechanism of ICB resistance in GC and highlights the WNT5A-SPP1+ macrophage pathway as a promising target to overcome immunotherapy resistance.