一种用于克服非小细胞肺癌治疗中抗原异质性的多靶向 CAR-T 细胞平台
A Multi-Targeting Chimeric Antigen Receptor-T Cell Platform to Overcome Antigen Heterogeneity in the Treatment of Non-Small Cell Lung Cancer.
这些发现支持采用多靶点CAR-T 策略来应对NSCLC及可能其他实体瘤中的抗原异质性。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
SLC2A1(+) 肿瘤相关巨噬细胞在空间上调控 CD8(+) T 细胞功能并驱动非小细胞肺癌的免疫治疗耐药
英文原题：SLC2A1(+) tumour-associated macrophages spatially control CD8(+) T cell function and drive resistance to immunotherapy in non-small-cell lung cancer.
查看英文原题
SLC2A1(+) tumour-associated macrophages spatially control CD8(+) T cell function and drive resistance to immunotherapy in non-small-cell lung cancer.
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中文摘要
肿瘤相关巨噬细胞（TAMs）促进免疫检查点阻断耐药，但其对瘤内CD8⁺ T细胞分布的影响仍不清楚。在此，我们表明葡萄糖转运蛋白SLC2A1的表达在非小细胞肺癌（NSCLC）活检和小鼠肿瘤模型中均与CD8⁺ T细胞分布呈空间负相关。肿瘤细胞特异性Slc2a1敲低无法重现SLC2A1抑制的治疗获益，而TAM特异性Slc2a1缺失通过增强瘤内CD8⁺ T细胞的空间均一性和效应功能抑制肿瘤生长，从而改善αPD-L1疗效。NSCLC标本的空间分析进一步揭示，SLC2A1⁺ TAM富集区域表现出CD8⁺ T细胞密度降低，且这些细胞群之间的空间邻近性预测对αPD-(L)1治疗的耐药。这些发现确定SLC2A1⁺ TAMs是空间性CD8⁺ T细胞排斥的驱动因素，并强调TAM特异性SLC2A1作为克服NSCLC免疫检查点阻断耐药的治疗靶点。
展开英文摘要原文
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.
论文信息
- 作者
- Wang L、Chu H、Chen D、Wei Y、Jia J、Li L、He L、Peng L
- 第一作者单位
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.China
- 通讯作者单位
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. qianchu@tjh.tjmu.edu.cn.China
- 期刊
- Nature cell biology2026 Feb
- 原文标识
- PubMed 41501177 · DOI 10.1038/s41556-025-01840-5
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