Fibroblast-specific ablation of MHC-I antigen presentation via the IGF2 axis cripples CD8⁺ T cell surveillance in lung cancer.

Authors

Daqiang Song, Xiaofang Li, Qian Xiao, Hongtao Tie, Qianxue Wu, Yu Shi, Guomin Ye, Jiazheng Sun, Jiazhou Liu, Mingjing Chen, Zhu Qiu, Weiyan Peng, Long Meng, Guosheng Ren, Jing Huang, Hongzhong Li

Published in

Science advances. Volume 12. Issue 29. Pages eaee5738. Jul 17, 2026. Epub Jul 17, 2026.

Abstract

How cancer-associated fibroblasts (CAFs) dictate CD8⁺ T cell dysfunction during lung cancer remains unclear. Through single-cell analysis of 84 human NSCLC samples, we identified insulin-like growth factor 2 (IGF2) as a key immunosuppressive factor in a specific CAF subset. IGF2⁺ CAF infiltration correlated with CD8⁺ T cell dysfunction. Fibroblast-specific IGF2 knockout enhanced antigen presentation cell-autonomously via major histocompatibility complex class I (MHC-I), boosting CD8⁺ T cell effector function, tumor suppression, survival, and PD-1 blockade synergy. Mechanistically, IGF2 sustained MYC signaling to up-regulate DNA methyltransferase 1 (DNMT1), which methylated the STAT1 promoter, epigenetically silencing STAT1. This impaired MHC-I presentation and CD8⁺ T cell activation. Clinically, high IGF2 levels associated with reduced CD8⁺ T cell cytotoxicity and poor outcomes. An IGF2⁺ fibroblast signature predicted worse response to immunotherapy in multiple cohorts. Our findings establish IGF2 as a central regulator of CAF-mediated immunosuppression and a stromal target for enhancing immunotherapy in lung cancer.

PMID:
42467784
Bibliographic data and abstract were imported from PubMed on 18 Jul 2026.

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