Traditional Chinese medicine reprograms the tumor microenvironment to overcome EGFR-TKI resistance: mechanisms and therapeutic perspectives

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have transformed the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). However, the inevitable emergence of acquired resistance significantly limits their long-term efficacy. While conventional accounts of resistance have primarily focused on tumor-intrinsic genetic alterations, accumulating evidence highlights the pivotal role of the tumor microenvironment (TME) in mediating therapeutic failure. The TME contributes to EGFR-TKI resistance through multiple interconnected mechanisms, including immunosuppression, extracellular matrix-mediated physical barriers, metabolic reprogramming, and compensatory signaling activation. These complex interactions create a protective niche that enables tumor cells to persist despite EGFR inhibition. Traditional Chinese medicine (TCM), characterized by its multi-component and multi-target properties, offers a potential systems-level approach to modulating the TME. Preclinical studies suggest that TCM-derived interventions may influence immune-cell polarization, stromal and vascular features, and tumor metabolism, thereby affecting EGFR-TKI sensitivity. This review focuses on TME-mediated EGFR-TKI resistance in NSCLC and appraises TCM interventions according to evidence type and directness. We evaluate current preclinical and clinical evidence, identify major limitations, and propose priorities for translational research. The review provides a conceptual framework for evaluating TCM-based combination strategies intended to attenuate EGFR-TKI resistance.