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Life sciences · Review
Frontiers in Oncology · November 5, 2026
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Gastrointestinal (GI) malignancies account for more than one-third of cancer-related deaths worldwide, and outcomes for advanced disease remain poor despite advances in systemic therapy and immunotherapy. Chimeric antigen receptor (CAR)-engineered cellular therapies have transformed the treatment of hematologic malignancies, but their application in solid tumors has been limited by antigen heterogeneity, immunosuppressive tumor microenvironments, on-target/off-tumor toxicity, and manufacturing challenges. This narrative review examines the clinical evidence supporting chimeric antigen receptor T-cell (CAR-T) and chimeric antigen receptor natural killer (CAR-NK) therapies directed against six major targets in GI oncology: claudin 18.2 (CLDN18.2), guanylyl cyclase C (GUCY2C), mesothelin (MSLN), glypican-3 (GPC3), carcinoembryonic antigen (CEA), and human epidermal growth factor receptor 2 (HER2). Among these, CLDN18.2 is the most advanced target; in the randomized phase II CT041-ST-01 trial, satricabtagene autoleucel significantly improved progression-free survival (PFS) compared with physician’s choice therapy in previously treated gastric or gastroesophageal junction cancer, providing the first randomized evidence of CAR-based therapy efficacy in a solid tumor. GUCY2C and GPC3 have shown promising early-phase activity in metastatic colorectal cancer and hepatocellular carcinoma, respectively, whereas mesothelin, CEA, and HER2 continue to face important biological and safety challenges. CAR-NK cells have emerged as a complementary platform with favorable safety characteristics and off-the-shelf manufacturing potential, although clinical experience in GI malignancies remains limited. We discuss the relative clinical maturity of these targets, key barriers to implementation, and emerging strategies that may advance the role of CAR-based cellular therapies in GI cancers.