Emerging Landscape of CAR-T Cell Therapy in Colon Cancer: Mechanistic Insights, Clinical Advances, Challenges, and Future Directions.

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematological malignancies; however, its clinical translation to solid tumors, including colon cancer, remains challenging. This review comprehensively examines the current landscape of CAR-T cell therapy for colon cancer, focusing on its underlying mechanisms, recent clinical advances, major challenges, and future perspectives. We provide an overview of CAR-T therapy, highlighting its significance in colorectal cancer and comparing its clinical performance in hematological malignancies and solid tumors. The review discusses the structural design and functional evolution of CAR-T cells, with particular emphasis on tumor-associated antigens such as epidermal growth factor receptor (EGFR), mucin-1 (MUC1), carcinoembryonic antigen (CEA), and Frizzled receptors. Mechanistic insights into the immunosuppressive tumor microenvironment and its impact on CAR-T cell efficacy are also presented. Despite promising preclinical and early clinical outcomes, several barriers continue to limit therapeutic success, including antigen heterogeneity, immune evasion, T-cell exhaustion, poor tumor infiltration, and manufacturing complexities. Current clinical trials targeting CEA, EGFR, and other emerging antigens are critically discussed to highlight recent progress and remaining limitations. In addition, we summarize emerging strategies to enhance CAR-T efficacy, including tumor microenvironment modulation, biomarker-guided patient selection, next-generation CAR designs, and combination therapies. Finally, we discuss future directions for optimizing CAR-T therapy through precision immunotherapy approaches, improved biomarker integration, and well-designed clinical trials. Overall, this review highlights the transformative potential of CAR-T cell therapy in colon cancer while providing a critical perspective on the challenges and opportunities that will shape its future clinical application.