Oncogene · 2026
Midkine-activated TRPA1+ cancer-associated fibroblasts promote immunotherapy resistance in gastric cancer through a WNT5A-mediated treg circuit.
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Zheng Hualong, Ye Xiaoqian, Zheng Linyong, Huang Xiaobo, Yan Haidan, Lin Zhilong, Zhong Qing, Tu Ruhong, Zhang Zhiquan, Gao Youxin, Huang Qiang, Li Yifan, Li Yi, Yang Xinpeng, Jiang Chenyang, Guo Xiaojing, Wang Maosen, Zheng Chaohui, Li Ping, Wang Jiabin, Lin Jianxian, Huang Changming, Chen Qiyue, Xie Jianwei
Аннотация
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.