c-MET Inhibition Is Accompanied by PD-L1 Upregulation and Immunosuppression-Related Tumor Microenvironment Changes in Esophageal Squamous Cell Carcinoma, With Enhanced Antitumor Activity in Combination With Anti-PD-1 Therapy.
- 1Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China.
Abstract
Background
c-MET is implicated in ESCC progression, but whether c-MET inhibition reshapes immune checkpoint expression and the tumor immune microenvironment remains unclear.Methods
ESCC cell lines were treated with Tepotinib, and c-MET and PD-L1 expression were examined by Western blotting and immunofluorescence. MET knockdown was performed in TE-1 and KYSE150 cells. AKR syngeneic subcutaneous tumor models were used to assess PD-L1 and PD-1 expression, immune cell composition, transcriptomic and proteomic changes, NF-κB/p65 signaling, and the efficacy of Tepotinib combined with an anti-PD-1 antibody.Results
Tepotinib decreased c-MET expression and increased PD-L1 expression in ESCC cells. MET knockdown produced a similar increase in PD-L1. In vivo, Tepotinib increased PD-L1 and PD-1 expression in tumor tissues and increased PD-L1 expression in the CD45⁻ non-immune compartment, together with decreased CD8⁺ T cells and cDC1 cells, increased Treg cells, and increased CD206 expression in tumor-associated macrophages. Dual immunofluorescence and quantitative analysis further showed an increased proportion of CD8⁺PD-1⁺ cells among total CD8⁺ cells in Tepotinib-treated tumors. Transcriptomic and proteomic analyses indicated enrichment of inflammatory and immune-related pathways, including NF-κB, TNF, JAK-STAT, and immune checkpoint-related signaling. Tepotinib increased p65 phosphorylation, whereas NF-κB inhibition reduced p-p65 and PD-L1 expression. Tepotinib combined with anti-PD-1 antibody reduced tumor burden and delayed humane endpoint events compared with monotherapy.Conclusions
c-MET inhibition is accompanied by adaptive PD-L1 upregulation and immunosuppression-related changes in the tumor microenvironment in ESCC. NF-κB/p65 signaling may participate in this response. The enhanced antitumor activity observed with Tepotinib plus anti-PD-1 therapy supports further investigation of this combination strategy.
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BibTeX
@article{song2026cmet,
title = {{c-MET Inhibition Is Accompanied by PD-L1 Upregulation and Immunosuppression-Related Tumor Microenvironment Changes in Esophageal Squamous Cell Carcinoma, With Enhanced Antitumor Activity in Combination With Anti-PD-1 Therapy.}},
author = {Chuan Song and Zhe Xia and Hu Wang and Xinyu Wang and Jing Li and Binbin Wang and Chen Feng and Bo Xie},
journal = {Cancer medicine},
year = {2026},
month = nov,
doi = {10.1002/cam4.72428},
url = {https://europepmc.org/article/MED/42968226},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - c-MET Inhibition Is Accompanied by PD-L1 Upregulation and Immunosuppression-Related Tumor Microenvironment Changes in Esophageal Squamous Cell Carcinoma, With Enhanced Antitumor Activity in Combination With Anti-PD-1 Therapy.
AU - Chuan Song
AU - Zhe Xia
AU - Hu Wang
AU - Xinyu Wang
AU - Jing Li
AU - Binbin Wang
AU - Chen Feng
AU - Bo Xie
PY - 2026
DA - 2026/11/01
JO - Cancer medicine
DO - 10.1002/cam4.72428
UR - https://europepmc.org/article/MED/42968226
AB - Background c-MET is implicated in ESCC progression, but whether c-MET inhibition reshapes immune checkpoint expression and the tumor immune microenvironment remains unclear.Methods ESCC cell lines were treated with Tepotinib, and c-MET and PD-L1 expression were examined by Western blotting and immunofluorescence. MET knockdown was performed in TE-1 and KYSE150 cells. AKR syngeneic subcutaneous tumor models were used to assess PD-L1 and PD-1 expression, immune cell composition, transcriptomic and proteomic changes, NF-κB/p65 signaling, and the efficacy of Tepotinib combined with an anti-PD-1 antibody.Results Tepotinib decreased c-MET expression and increased PD-L1 expression in ESCC cells. MET knockdown produced a similar increase in PD-L1. In vivo, Tepotinib increased PD-L1 and PD-1 expression in tumor tissues and increased PD-L1 expression in the CD45⁻ non-immune compartment, together with decreased CD8⁺ T cells and cDC1 cells, increased Treg cells, and increased CD206 expression in tumor-associated macrophages. Dual immunofluorescence and quantitative analysis further showed an increased proportion of CD8⁺PD-1⁺ cells among total CD8⁺ cells in Tepotinib-treated tumors. Transcriptomic and proteomic analyses indicated enrichment of inflammatory and immune-related pathways, including NF-κB, TNF, JAK-STAT, and immune checkpoint-related signaling. Tepotinib increased p65 phosphorylation, whereas NF-κB inhibition reduced p-p65 and PD-L1 expression. Tepotinib combined with anti-PD-1 antibody reduced tumor burden and delayed humane endpoint events compared with monotherapy.Conclusions c-MET inhibition is accompanied by adaptive PD-L1 upregulation and immunosuppression-related changes in the tumor microenvironment in ESCC. NF-κB/p65 signaling may participate in this response. The enhanced antitumor activity observed with Tepotinib plus anti-PD-1 therapy supports further investigation of this combination strategy.
SN - 2045-7634
ER -