Advances and challenges in immunotherapy for advanced esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is a highly prevalent and aggressive malignancy worldwide, associated with poor prognosis. Most patients are diagnosed at an advanced stage, where conventional chemotherapy offers limited therapeutic efficacy and is often accompanied by substantial toxicity. In recent years, immune checkpoint inhibitors (ICIs), particularly those targeting PD-(L)1 and CTLA-4, have emerged as cornerstone therapies in both first-line and subsequent treatment settings for advanced ESCC. Nevertheless, significant clinical challenges persist, including the complexity of mechanisms underlying immune resistance, suboptimal predictive performance of existing biomarkers, difficulties in the management of immune-related adverse events (irAEs), and underrepresentation of elderly patients in clinical trials. This review summarizes recent advances in immunotherapy for advanced ESCC, evaluating the clinical evidence supporting ICIs as monotherapy or in combination with agents such as anti-angiogenic drugs and tyrosine kinase inhibitors. It further discusses the therapeutic potential of novel approaches, including bispecific antibodies, CAR-T cell therapy, and next-generation ICIs, while addressing current treatment paradigms for elderly patients. The importance of comprehensive, longitudinal management of irAEs is emphasized. Additionally, this article provides an in-depth analysis of mechanisms contributing to immune resistance-such as loss of tumor neoantigens and dysregulation of key signaling pathways-and critically appraises the limitations of established biomarkers, including PD-L1 expression and tumor mutational burden (TMB), alongside emerging developments in biomarker discovery. In conclusion, while immunotherapy has significantly improved outcomes and expanded therapeutic prospects for patients with advanced ESCC, further research is required to elucidate resistance mechanisms, refine treatment strategies, and identify robust predictive biomarkers. These efforts are essential to advance precision medicine in ESCC and ultimately enhance long-term survival outcomes.