Immunosuppressive tumor microenvironment and immunotherapy resistance of esophageal carcinoma

Esophageal carcinoma (EC) remains one of the most lethal malignancies, with a five-year survival rate of only 15-25% in advanced stages. Although immunotherapy including immune checkpoint inhibitors (ICIs) and antibody-based therapies have improved clinical outcomes, durable responses are confined to a minority of patients because primary and acquired resistance affect the majority. The tumor microenvironment (TME)—composed of immune cells, stromal cells, and the extracellular matrix—has emerged as a central driver of the immune resistance, wherein infiltrating immune cells and stromal cells form suppressive networks that impair cytotoxic immunity and foster tumor progression. However, a coherent framework linking clinical practice, TME-mediated resistance mechanisms, and therapeutic strategies remains lacking. In this review, we dissect the cellular and molecular basis of TME-driven immune resistance in EC, summarize established and emerging immunotherapies, and evaluate strategies to overcome treatment failure, including TME-targeted therapy, metabolic modulation, photodynamic therapy, and mechanism-guided combination approaches. These insights reframe immunotherapy resistance as a TME-driven process rather than a purely tumor-intrinsic defect, underscoring the need to concurrently target malignant cells and their surrounding immunosuppressive niche. Ultimately, elucidating TME heterogeneity and its dynamic evolution is essential to convert resistant EC into an immunotherapy-responsive disease and to guide precision combination strategies.