SLC2A1+ tumour-associated macrophages spatially control CD8+ T cell function and drive resistance to immunotherapy in non-small-cell lung cancer

作者：Lei Wang, Han Chu, Degao Chen, Yuxuan Wei, Jia Jia, Liqi Li, Linfeng He, Lina Peng, Fangfang Liu, Shanshan Huang, Zheng Jin, Dong Zhou, WenFeng Fang, Tao Jiang, Shouxia Xu, Xiaofang Ding, Haoyang Cai, Xindong Liu, Qingzhu Jia, BO ZHU, Qian Chu · 发表于：Nature Cell Biology · 年份：2026 · DOI：10.1038/s41556-025-01840-5 · 被引用次数：8 · 研究领域：Immune cells in cancer、Cancer Immunotherapy and Biomarkers、Cancer, Hypoxia, and Metabolism

Tumour-associated macrophages (TAMs) contribute to immune checkpoint blockade resistance, but their impact on intratumoural CD8⁺ T cell distribution remains unclear. Here we show that the expression of the glucose transporter SLC2A1 is spatially negatively correlated with CD8⁺ T cell distribution in both non-small-cell lung cancer (NSCLC) biopsies and murine tumour models. Tumour cell-specific Slc2a1 knockdown fails to reproduce the therapeutic benefit of SLC2A1 inhibition, whereas TAM-specific deletion of Slc2a1 suppresses tumour growth by enhancing the spatial homogeneity and effector function of intratumoural CD8⁺ T cells, thereby improving αPD-L1 efficacy. Spatial profiling of NSCLC specimens further revealed that SLC2A1⁺ TAM-enriched regions exhibit reduced CD8⁺ T cell density, and spatial proximity between these populations predicts resistance to αPD-(L)1 therapy. These findings identify SLC2A1⁺ TAMs as drivers of spatial CD8⁺ T cell exclusion and highlight TAM-specific SLC2A1 as a therapeutic target to overcome immune checkpoint blockade resistance in NSCLC. Wang, Chu, Chen, Wei and colleagues discover a subset of tumour-associated macrophages expressing SLC2A1 whose spatial proximity to CD8+ T cells drives resistance to anti-PD-L1 treatment in non-small-cell lung cancer.