From Mechanisms to Therapeutic Innovation in Non-Small-Cell Lung Cancer: A Knowledge-Depth Translational Mapping with Experimental Validation

Background: Non-small-cell lung cancer (NSCLC) research has transitioned from tumor-intrinsic mechanisms to immune-driven therapeutic innovation; however, the translation of mechanistic insights into clinically actionable strategies remains incompletely defined. Methods: A total of 1213 records were retrieved from the Web of Science Core Collection (SCI-Expanded) (2009–2025). After data cleaning and duplicate removal (n = 13), 1200 publications were analyzed. Bibliometrix (R) and CiteSpace were used for performance analysis, keyword mapping, thematic evolution, and co-citation clustering. Results: Annual scientific production increased markedly after 2018, paralleling the expansion of immunotherapy. Keyword co-occurrence identified three major thematic domains (>40 high-frequency keywords) linking molecular mechanisms, biomarkers, and therapeutic strategies. Thematic mapping highlighted immunotherapy, tumor microenvironment, and PD-1 as dominant motor themes, while resistance-related pathways formed a central mechanistic–translational axis. Thematic evolution demonstrated a shift from EGFR-targeted therapy to epithelial–mesenchymal transition (EMT)-centered resistance and subsequently to immune-dominant strategies. Co-citation clustering produced robust structures (Q ≈ 0.62; silhouette ≈ 0.84), identifying EMT as a persistent mechanistic hub. Pilot ELISA validation confirmed significant increases in TGF-β1 (~2.05-fold), IL-6 (~2.59-fold), CCL2 (~2.10-fold), and PD-L1 (~2.56-fold) under EMT-inducing conditions (p < 0.01). Conclusions: This integrative approach provides a quantitative and experimentally supported framework linking mechanistic insights to therapeutic innovation in NSCLC.