Emerging landscape of CAR T-cell therapy in gastrointestinal malignancies: A systematic review of clinical trials.

322 Background: CAR T-cell therapy has transformed hematologic malignancies, but its role in gastrointestinal (GI) cancers remains exploratory. Antigen heterogeneity, tumor microenvironment suppression, and safety concerns have limited progress. We aimed to review all ongoing CAR T clinical trials in GI cancers to evaluate therapeutic targets, outcomes, and challenges. Methods: A systematic review of PubMed and ClinicalTrials.gov was conducted through July 2025. Trials were included if they investigated CAR T therapy in GI cancers. Data were extracted on tumor type, antigen target, trial phase, and reported outcomes. Results: We identified 31 active or completed trials of CAR T-cell therapy in GI malignancies. In esophageal and gastroesophageal junction cancers, mesothelin-targeted CAR T (NCT05239143) is under early-phase evaluation, while CLDN18.2-directed CAR T demonstrated a 40% survival improvement in advanced gastric/GEJ adenocarcinoma. Gastric cancer trials also include HER2- and MUC1-directed CAR Ts with early safety data. In colorectal cancer, CAR T constructs targeting CEA, EpCAM, and NKG2DL have shown feasibility but modest clinical responses. Pancreatic cancer studies with mesothelin, PSCA, and MUC1 CAR Ts (NCT03323944) report manageable safety and disease stabilization in select cases. In hepatocellular carcinoma, GPC3-directed CAR T therapy demonstrated partial responses in early Chinese trials, while EpCAM- and MUC1-targeted CAR Ts are being studied in cholangiocarcinoma. Overall, clinical efficacy remains limited, but safety has improved with regional delivery approaches and next-generation CAR designs. Conclusions: CAR T-cell therapy in GI cancers is at an early stage but demonstrates encouraging signals, particularly with CLDN18.2-targeted constructs in gastric/GEJ adenocarcinoma and mesothelin-directed CAR Ts in pancreatic and esophageal cancers. Integration of CAR T with checkpoint blockade, armored CAR designs, and biomarker-guided antigen selection may overcome barriers and expand therapeutic opportunities across GI malignancies.