The evolving immune ecosystem of TKI resistance in EGFR-mutant NSCLC: from treatment-induced remodeling to mechanism-guided therapy
Abstract
Tyrosine kinase inhibitors (TKIs) have transformed the treatment of EGFR-mutant non-small cell lung cancer (NSCLC), yet acquired resistance remains a major clinical limitation. Resistance is increasingly understood as an evolving state shaped not only by tumor-cell genomic alterations but also by treatment-induced remodeling of the tumor immune microenvironment (TIME). This Review examines how EGFR-TKI exposure reshapes macrophage states, T-cell function and localization, fibroblast and myeloid niches, and vascular architecture, and how these changes are reinforced by immune-checkpoint adaptation, metabolic reprogramming, and phenotypic plasticity. We then connect the evolving TIME to post-TKI therapeutic strategies according to the maturity of the supporting evidence, including immune checkpoint inhibitor-containing regimens, anti-angiogenic combinations, mechanism-matched targeted therapy, antibody-drug conjugates, bispecific T-cell engagers, and selected preclinical microenvironment-directed approaches. Finally, we discuss circulating biomarkers, single-cell sequencing, and spatial profiling as tools for longitudinally defining resistant immune states. Viewing TKI resistance as a temporally evolving immune ecosystem provides a framework for linking resistance mechanism, immune phenotype, and treatment selection rather than treating progression as a purely genomic endpoint.
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BibTeX
@article{luo2026evolving,
title = {{The evolving immune ecosystem of TKI resistance in EGFR-mutant NSCLC: from treatment-induced remodeling to mechanism-guided therapy}},
author = {Biyuan Luo and Alifujiang Hairulajiang and Jiayi Liu and Xianling Liu},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1990429},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1990429},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The evolving immune ecosystem of TKI resistance in EGFR-mutant NSCLC: from treatment-induced remodeling to mechanism-guided therapy
AU - Biyuan Luo
AU - Alifujiang Hairulajiang
AU - Jiayi Liu
AU - Xianling Liu
PY - 2026
DA - 2026/11/09
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1990429
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1990429
AB - Tyrosine kinase inhibitors (TKIs) have transformed the treatment of EGFR-mutant non-small cell lung cancer (NSCLC), yet acquired resistance remains a major clinical limitation. Resistance is increasingly understood as an evolving state shaped not only by tumor-cell genomic alterations but also by treatment-induced remodeling of the tumor immune microenvironment (TIME). This Review examines how EGFR-TKI exposure reshapes macrophage states, T-cell function and localization, fibroblast and myeloid niches, and vascular architecture, and how these changes are reinforced by immune-checkpoint adaptation, metabolic reprogramming, and phenotypic plasticity. We then connect the evolving TIME to post-TKI therapeutic strategies according to the maturity of the supporting evidence, including immune checkpoint inhibitor-containing regimens, anti-angiogenic combinations, mechanism-matched targeted therapy, antibody-drug conjugates, bispecific T-cell engagers, and selected preclinical microenvironment-directed approaches. Finally, we discuss circulating biomarkers, single-cell sequencing, and spatial profiling as tools for longitudinally defining resistant immune states. Viewing TKI resistance as a temporally evolving immune ecosystem provides a framework for linking resistance mechanism, immune phenotype, and treatment selection rather than treating progression as a purely genomic endpoint.
SN - 1664-3224
ER -