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September 10, 2025Advanced Science13 citationsOpen Access

EGFR: New Insights on Its Activation and Mutation in Tumor and Tumor Immunotherapy

YGYuanzhuo Gu HHHongchao HeThe University of Texas MD Anderson Cancer Center SQShuang QiaoHuzhou University

Key Points

Activation of the EGFR gene impacts tumor response to immunotherapy and treatment effectiveness.
The review highlights the role of both tumor-intrinsic and tumor-extrinsic factors in EGFR's impact on immunotherapy.
Different EGFR mutations result in varied responses to immune checkpoint blockades in cancer treatments.
Current strategies for targeting EGFR in combination with immunotherapy may enhance anticancer drug effectiveness.

Abstract

The success of immune checkpoint blockades (ICBs) has accelerated the clinical implementation of multiple single agents and combination immunotherapies, but the response rates vary. Reconsideration of immune-oncology therapeutic failures via perspective from tumor-intrinsic (such as oncogenic driver genes) and tumor-extrinsic (the complexity of immune cell-cancer cell interactions) may help to better design more effective anticancer drugs and treatment strategies. Herein, in this review, introducing the frequently mutated gene EGFR in tumors and its abnormal activation are mainly focused on, highlighting that epidermal growth factor receptor (EGFR) wild-type and mutants respond differently to ICBs via tumor-intrinsic and tumor-extrinsic manners. Through briefly reviewing how EGFR is activated and the current EGFR targeting strategy, the present clinical trials of combination with EGFR inhibitors and ICBs are summarized, and the mechanism by which EGFR affects immunotherapy and measures to improve the efficacy of immunotherapy are discussed.

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