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, Li-Qi Li, Linfeng He, L. Peng, Fangfang Liu, Shanshan Huang, Zheng Jin, Dong Zhou, Wen-Feng Fang, Tao Jiang, Shouxia Xu, Xiaofang Ding, Haoyang Cai, Xindong Liu, Q. 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：14 · 研究领域：Medicine

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.