尽管免疫疗法可以延长一些头颈鳞状细胞癌（HNSCC）患者的生存期，但缓解率仍然较低。阐明肿瘤微环境中调节 CD8 T 细胞浸润和功能障碍的关键机制有助于最大限度地发挥免疫疗法治疗 HNSCC 的益处。在这里，我们对具有不同免疫浸润的 HNSCC 标本进行了空间转录组分析，并对五对肿瘤和邻近组织进行了单细胞 RNA 测序，揭示了与 CD8 T 细胞浸润限制和功能障碍相关的特定 CAF 亚群。这些 CAF 表现出 CXCL（CXCL9、CXCL10、CXCL12）和主要组织相容性复合物 I 类 (MHC-I) 的高表达以及半乳糖凝集素 9 (Gal-9) 的富集。 MHC-IhiGal-9 CAF 的比例与 CD8 T 细胞 TCF1 GZMK 子集的丰度呈负相关。 CAF 上的 Gal-9 诱导 CD8 T 细胞功能障碍并降低肿瘤浸润 TCF1 CD8 T 细胞的比例。总的来说，MHC-IhiGal-9 CAF 的鉴定促进了对 CAF 在癌症免疫逃避中精确作用的理解，并为更有效的 HNSCC 免疫治疗铺平了道路。

Although immunotherapy can prolong survival in some patients with head and neck squamous cell carcinoma (HNSCC), the response rate remains low. Clarification of the critical mechanisms regulating CD8+ T-cell infiltration and dysfunction in the tumor microenvironment could help maximize the benefit of immunotherapy for treating HNSCC. Here, we performed spatial transcriptomic analysis of HNSCC specimens with differing immune infiltration and single-cell RNA sequencing of five pairs of tumor and adjacent tissues, revealing specific CAF subsets related to CD8+ T-cell infiltration restriction and dysfunction. These CAFs exhibited high expression of CXCLs (CXCL9, CXCL10, CXCL12) and major histocompatibility complex class I (MHC-I) and enrichment of galectin-9 (Gal-9). The proportion of MHC-IhiGal-9+ CAFs was inversely correlated with abundance of a TCF1+GZMK+ subset of CD8+ T cells. Gal-9 on CAFs induced CD8+ T cell dysfunction and decreased the proportion of tumor-infiltrating TCF1+CD8+ T cells. Collectively, the identification of MHC-IhiGal-9+ CAFs advances the understanding of the precise role of CAFs in cancer immune evasion and paves the way for more effective immunotherapy for HNSCC.