Gastric cancer tertiary lymphoid structures in the muscularis propria are associated with therapy resistance and promote immunosuppression

作者：Yan Meng, Meng Wang, 龙满美, Yantao Duan, Jingwu Yue, Delin Zou, Weihong Zhang, Mingquan Li, Ruixian Yu, Lin Shao, Xinyu Yang, Yi Han, Wenjia Wang, Jianfeng Chen, Miao He, Yang Tang, Zongwei Chen, Wei Kang, Ka‐Fai To, Zhaocai Zhou, Dazhi Xu, Hui Li, Shi Jiao · 发表于：Nature Communications · 年份：2026 · DOI：10.1038/s41467-026-77267-9 · 研究领域：Cancer Immunotherapy and Biomarkers、Immune cells in cancer、Cancer Cells and Metastasis

Tertiary lymphoid structures (TLS) are local immune microenvironments within tumors housing T cells and B cells, are often coordinating anti-tumor immunity and associated with better responses to immunotherapy. Here, we use H&E morphological assessment and multiplex immunofluorescence to analyze surgical tumor specimens from 71 patients with gastric cancer (GC) after treatment with neoadjuvant anti-PD-1 therapy, chemotherapy, and subsequent gastrectomy. We find increased TLS density and area in the muscularis propria of treatment-resistant GCs. These muscularis TLS are structurally and functionally impaired, with increased naïve B cell presence but reduced germinal center B cell infiltration. Mechanistically, PLA2G2A+ tumor cells accumulate adjacent to disrupted muscularis TLS, and PLA2G2A treatment in vitro increases differentiation of a fibroblast cell line into PDGFRA+ inflammatory cancer-associated fibroblasts (iCAF), which are linked to CXCL14 secretion and recruitment of naïve B cells. In vitro, PLA2G2A also impairs B cell differentiation and induces T follicular helper cell death, potentially contributing to muscularis TLS dysfunction. Taken together, we propose a tumor cell-iCAF-B cell axis disrupting TLS function, with this axis serving as a potential therapeutic target to overcome immunotherapy resistance. Tertiary lymphoid structures (TLS) are thought to orchestrate anti-tumor immunity and support immunotherapy. Here, the authors find dysfunctional TLS in the muscu...