Harnessing the chimeric antigen receptor engineered cells in gastrointestinal cancer immunotherapy

Gastrointestinal (GI) cancers pose a significant global health concern. Their prevalence is continually increasing, and managing them remains a significant clinical hurdle. Adoptive cell therapies designed to express chimeric antigen receptors (CARs) or transgenic T cell receptors (TCRs) to identify and destroy cancer cells have emerged as a promising strategy for achieving long-term remissions in cancer patients. To be effective, the engineered cells must persist at therapeutically sufficient levels while minimizing off-tumor toxicities, which has proven difficult to realize outside of hematologic malignancies. This review comprehensively discusses the progress and use of CAR-immune cells in treating GI cancers. We looked into different sources of these cells, CAR design strategies, and the latest advancements in CAR-cell therapy for GI cancers, while providing organ-specific preclinical and clinical insights across colorectal, gastric, hepatic, and pancreatic malignancies. Moreover, we discussed the current challenges and suggested potential methods to improve the efficacy and safety of CAR-cell therapy. This review emphasizes the unique potential of CAR-NK cells as low-toxicity, "off-the-shelf" alternatives to CAR-T cells. It details innovative strategies to overcome solid tumor challenges-including metabolic reprogramming, dual-targeting approaches, and microenvironment modulation. It is concluded that CAR cells have significant potential to revolutionize the treatment of gastrointestinal cancer, paving the way for rational combinations that open up new therapeutic perspectives.