From EGFR mutations to STAT30-driven resistance in NSCLC: Biomarkers and multi-modal treatment approach

Non–small-cell lung cancer (NSCLC) accounts for approximately 85 % of lung cancer cases and remains the leading cause of cancer mortality worldwide. However, the emergence of drug resistance and tumor immune evasion limits long-term treatment efficacy and reduces overall patient survival. We examine how activating EGFR mutations or overexpression induce STAT3 phosphorylation and regulate transcription factors such as Snail, Twist, and ZEB1. Next, we critically evaluate therapies ranging from first- to third-generation EGFR tyrosine kinase inhibitors and novel STAT3 antagonists to immune checkpoint inhibitors. Although numerous preclinical studies demonstrate synergistic activity when EGFR-TKIs are combined with STAT3 inhibitors or ICIs, clinical trial data remain sparse and preliminary. Preclinical studies of Polyphyllin I and MTI31 illustrate the reversal of epithelial-mesenchymal transition and restoration of sensitivity to EGFR-targeted agents. In contrast to previous reviews, we offer a comparative analysis of monotherapy versus combination regimens, highlight remaining knowledge gaps, and propose an integrated framework for co-targeting EGFR, STAT3, and immune checkpoints. We aim to elucidate EGFR–STAT3 signaling crosstalk in NSCLC and distinguish preclinical findings from clinical data to enhance the translational relevance of combination therapies.