Faculty, Staff and Student Publications

Publication Date

7-15-2025

Journal

Cell Reports Medicine

DOI

10.1016/j.xcrm.2025.102194

PMID

40543507

PMCID

PMC12281364

PubMedCentral® Posted Date

6-20-2025

PubMedCentral® Full Text Version

Post-print

Abstract

The introduction of immunotherapy as a first-line treatment for advanced small cell lung cancer (SCLC) represents significant progress, yet there remains an opportunity to further improve patient outcomes. Hepatocyte growth factor (HGF) receptor (MET) pathway activation promotes epithelial-mesenchymal transition, driving chemoresistance and potentially impairing the efficacy of immunotherapy. In SCLC mouse models, adding MET inhibition to chemo-immunotherapy (anti-PD-L1) reduces tumor growth, extends survival, and reshapes the tumor microenvironment by decreasing suppressive myeloid cell infiltration and enhancing the immune response. Analysis of pretreatment human SCLC tumor samples reveals that myeloid-enriched immune infiltrates may contribute to chemo-immunotherapy resistance. Elevated serum HGF levels are associated with a mesenchymal and inflamed phenotype, suggesting that patients with these characteristics might benefit from MET inhibitor-based therapeutic strategies. These findings provide strong preclinical and translational evidence supporting MET inhibition as a therapeutic approach to overcome treatment resistance, enhancing the immune response and improving outcomes in biomarker-defined subsets of SCLC patients.

Keywords

Small Cell Lung Carcinoma, Humans, Proto-Oncogene Proteins c-met, Animals, Lung Neoplasms, Immunotherapy, Mice, Tumor Microenvironment, Hepatocyte Growth Factor, Signal Transduction, Cell Line, Tumor, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition, Female, Xenograft Model Antitumor Assays, B7-H1 Antigen, small cell lung cancer, MET inhibitor, immune checkpoint inhibitor, epithelial-mesenchymal transition, myeloid-derived suppressor cells

Published Open-Access

yes

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