EGFR activation disrupts immunotherapy response via SHP2-mediated suppression of tumor-intrinsic response to IFN-γ

作者：Wei-Tao Zhuang, Lan-Lan Pang, Li-Yang Hu, Jun Liao, Jianhua Zhan, Ting Yong Li, Ri-Xin Chen, Jia-Ni Zheng, An-Lin Li, Wen-Yan Yu, Tian-Qin Mao, Liang Chen, Yu-Jian Huang, Shaodong Hong, Jing Li, Jun-Han Wu, Yi-Ming Zeng, Meng‐Juan Yang, Hai-qing Zeng, Yaxiong Zhang, Li Zhang, Wenfeng Fang · 发表于：Journal of Clinical Investigation · 年份：2026 · DOI：10.1172/jci194377 · 被引用次数：3 · 研究领域：Cancer Immunotherapy and Biomarkers、Protein Tyrosine Phosphatases、Lung Cancer Treatments and Mutations

Epidermal growth factor receptor-activating (EGFR-activating) mutations are established biomarkers of resistance to immune checkpoint blockade (ICB) in lung cancer, yet the precise molecular mechanism and effective therapeutic strategies remain elusive. In this study, we show that EGFR overexpression and amplification recapitulated the negative effect of EGFR driver mutations on the ICB response, indicating a proactive involvement of EGFR signaling in antagonizing the antitumor immune response. Functional studies unveiled that EGFR activation suppressed the cellular response to IFN-γ following ICB treatment across multiple cancer models. This impairment in IFN-γ responsiveness further limited the upregulation of T cell-recruiting chemokines and antigen presentation, resulting in reduced T cell infiltration and activation, ultimately undermining antitumor immunity. Mechanistically, EGFR promotes Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) activation to accelerate STAT1 dephosphorylation, leading to premature termination of the IFN-γ response. SHP2 inhibition restored ICB sensitivity in EGFR-activated tumors, significantly reducing tumor burden while maintaining a favorable safety profile. Our findings suggest that the EGFR/SHP2 axis functions as a molecular brake to disrupt the initiation and amplification of the IFN-γ-mediated antitumor response during immunotherapy. This discovery unveils a potential avenue to overcome immunotherapy resistance in EGFR-dri...