{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:52:49Z","timestamp":1791287569209,"version":"4.1.0"},"reference-count":177,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1973515","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:11:12Z","timestamp":1791285072000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular mechanisms and therapeutic strategies of immunotherapy resistance in esophageal cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Yiqian","family":"Pang","sequence":"first","affiliation":[{"name":"Key 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","place":["Luoyang, 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