Beyond monotherapy: The evolving role of CTLA-4 in combination immunotherapy for gastrointestinal cancers

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a key immune checkpoint in Gastrointestinal system cancers (GSCs), inhibiting T-cell activation by outcompeting CD28 for B7-1/B7-2 binding on antigen-presenting cells, thereby promoting immune evasion. Its overexpression correlates with advanced stage, poor survival, and worse prognosis in gastric, colorectal, esophageal, and pancreatic cancers. CTLA-4 blockade with Ipilimumab or Tremelimumab shows promise, especially combined with PD-1/PD-L1 inhibitors, yielding enhanced antitumor immunity in microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) tumors with high immune infiltration. However, efficacy is limited by tumor heterogeneity and an immunosuppressive microenvironment enriched in CTLA-4⁺ regulatory T cells (Tregs). Inconsistent clinical responses underscore the need for predictive biomarkers, optimized combinations, and mechanistic insights into resistance. This review explores CTLA-4's role in GSCs, highlighting microenvironment-focused strategies to improve precision and therapeutic outcomes.