Exploring novel immunotherapy in advanced esophageal squamous cell carcinoma: Is targeting TIGIT an answer?

Esophageal squamous cell carcinoma (ESCC) is a prevalent and highly lethal malignancy in Asia. Recent advancements in immune checkpoint inhibitors (ICIs) have markedly transformed the systemic therapy landscape for ESCC. Anti-PD-1-based combination with chemotherapy or with ipilimumab, an anti-CTLA-4 antibody, have been established as the new standard first-line treatments for patients with advanced ESCC. Moreover, anti-PD-1 monotherapy has demonstrated improved efficacy and survival compared with second-line chemotherapy in previously treated patients with ESCC. Novel ICIs targeting other immune checkpoints also show potential for enhancing anticancer therapy in advanced ESCC.The TIGIT/PVR pathway represents a new immune checkpoint. Preclinical studies have indicated that the dual blockade of TIGIT and PD-1 can enhance antitumor immune responses. Clinical trials have reported that combining anti-TIGIT with anti-PD-1/PD-L1 antibodies elicited clinical responses in patients with advanced ESCC. In the first-line systemic therapy setting, combinations of dual ICIs targeting TIGIT and PD-1/PD-L1 plus platinum-based chemotherapy have demonstrated acceptable toxicity profiles and promising antitumor activity in several phase II trials and one phase III study. However, the role of adding an anti-TIGIT antibody to the current standard of anti-PD-1/PD-L1 plus platinum-based chemotherapy in first-line therapy for advanced ESCC remains to be fully determined, necessitating further clinical trials. Ongoing studies are also investigating the role of anti-TIGIT, with or without anti-PD-1/PD-L1, in locoregional ESCC. Additional research is essential to optimize the potential of anti-TIGIT therapy in ESCC and other malignancies by identifying predictive biomarkers, determining optimal antibody types, and gaining key mechanistic insights.