Molecular mechanisms and therapeutic strategies of immunotherapy resistance in esophageal cancer.

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.