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Peer-reviewedCC BY 4.0Frontiers in Immunology

Molecular mechanisms and therapeutic strategies of immunotherapy resistance in esophageal cancer

  • Yiqian Pang1
  • Panpan Jiang1
  • Ke Liu1
  • Xingyao Suo1
  • Dianbao Zhang1
  • Yishi Xu1
  • Yi Ge1
  • Qizhi Fu1
  • Shegan Gao1,2
  1. 1Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology
  2. 2Institute of Organoid on Chip and Drug Translation Research, Henan Academy of Sciences
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Abstract

Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has transformed the treatment landscape for advanced esophageal cancer (EC). Nevertheless, clinical benefits are constrained by primary and acquired resistance driven by a dynamic immunosuppressive tumor microenvironment (TME), extensive metabolic reprogramming, and epigenetic dysregulation. This review provides a comprehensive analysis of the molecular mechanisms underlying immunotherapy resistance in EC, including TME remodeling by cancer-associated fibroblasts, tumor-associated macrophages, and immunosuppressive cell populations; metabolic reprogramming encompassing glucose, amino acid, and lipid metabolism; epigenetic regulation involving DNA methylation, histone modifications, and non-coding RNAs; and compensatory immune checkpoint upregulation. We further highlight the emerging role of the microbiome and critically evaluate combination strategies designed to overcome resistance, including anti-angiogenic agents, ADCs, and personalized approaches guided by multi-omics and organoid models.

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Cite

BibTeXRIS
BibTeX
@article{pang2026molecular,
  title = {{Molecular mechanisms and therapeutic strategies of immunotherapy resistance in esophageal cancer}},
  author = {Yiqian Pang and Panpan Jiang and Ke Liu and Xingyao Suo and Dianbao Zhang and Yishi Xu and Yi Ge and Qizhi Fu and Shegan Gao},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1973515},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1973515/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Molecular mechanisms and therapeutic strategies of immunotherapy resistance in esophageal cancer
AU  - Yiqian Pang
AU  - Panpan Jiang
AU  - Ke Liu
AU  - Xingyao Suo
AU  - Dianbao Zhang
AU  - Yishi Xu
AU  - Yi Ge
AU  - Qizhi Fu
AU  - Shegan Gao
PY  - 2026
DA  - 2026/10/06
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1973515
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1973515/full
AB  - Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has transformed the treatment landscape for advanced esophageal cancer (EC). Nevertheless, clinical benefits are constrained by primary and acquired resistance driven by a dynamic immunosuppressive tumor microenvironment (TME), extensive metabolic reprogramming, and epigenetic dysregulation. This review provides a comprehensive analysis of the molecular mechanisms underlying immunotherapy resistance in EC, including TME remodeling by cancer-associated fibroblasts, tumor-associated macrophages, and immunosuppressive cell populations; metabolic reprogramming encompassing glucose, amino acid, and lipid metabolism; epigenetic regulation involving DNA methylation, histone modifications, and non-coding RNAs; and compensatory immune checkpoint upregulation. We further highlight the emerging role of the microbiome and critically evaluate combination strategies designed to overcome resistance, including anti-angiogenic agents, ADCs, and personalized approaches guided by multi-omics and organoid models.
SN  - 1664-3224
ER  -