Multi-Omics-Enabled Precision Strategies for Overcoming CAR-T Therapy Limitations in Gastrointestinal Malignancies

Gastrointestinal malignancies, including gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, remain major causes of cancer-related morbidity and mortality worldwide. Although chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic malignancies, its efficacy in gastrointestinal solid tumors remains limited by antigen heterogeneity, insufficient trafficking and infiltration, immunosuppressive tumor microenvironments, on-target off-tumor toxicity, and adaptive resistance. In this review, we summarize the current landscape of CAR-T therapy in gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer, with a focus on representative target antigens and emerging biomarker strategies. We further discuss two major categories of biomarkers: target antigen-related biomarkers and conventional dynamic biomarkers, including serum tumor markers, cytokine changes, CAR-T expansion kinetics, and antigen-loss monitoring. In addition, we highlight how single-cell ribonucleic acid sequencing and spatial transcriptomics provide complementary insights into cellular states, immune exhaustion, stromal barriers, and spatially restricted immune exclusion. By integrating these multi-omics approaches with biomarker-guided patient stratification and next-generation CAR-T engineering, gastrointestinal solid tumor CAR-T therapy may evolve from empirical optimization toward mechanism-driven and precision-guided clinical translation.