Unmasking immune checkpoint resistance in esophageal squamous cell carcinoma: Insights into the tumor microenvironment and biomarker landscape

Esophageal squamous cell carcinoma (ESCC) remains a daunting global health concern. It is marked by aggressive progression and poor survival. While immunotherapy has emerged as a promising treatment modality, both primary and acquired resistance continue to limit its clinical impact, leaving many patients without durable benefits (e.g., CheckMate-648, ESCORT-1st). This review explains resistance mechanisms and suggests new strategies to improve outcomes. These mechanisms include immunosuppressive cells (Treg cells, myeloid-derived suppressor cells), inhibitory cytokines, molecular alterations involving programmed death 1/programmed death-ligand 1 signaling, and impaired antigen presentation. We also highlight key clinical trials—for example, CheckMate-648 and ESCORT-1st—that reveal both the potential and pitfalls of current immune checkpoint blockade strategies, underscoring the need for robust predictive biomarkers. Moreover, we examine cutting-edge tactics to overcome resistance, including combination regimens, tumor microenvironment remodeling, and tailored treatment approaches rooted in the patient’s unique genomic and immunologic landscape.