The evolving immune ecosystem of TKI resistance in EGFR-mutant NSCLC: from treatment-induced remodeling to mechanism-guided therapy

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.