Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide and remains a major treatment challenge, particularly in advanced and metastatic stages. Current standard treatments have limited efficacy, underscoring the urgent need for innovative strategies. Adoptive cell therapy (ACT), which involves in vitro expansion or genetic engineering of immune cells, is a promising approach to bolster anti-tumor immune responses. Key ACT modalities include chimeric antigen receptor (CAR) T cells, tumor-infiltrating lymphocytes (TILs), and T cell receptor (TCR)-engineered T cells. CAR-T cell therapy has shown success in hematological malignancies but faces significant challenges in solid tumors like CRC. These challenges include antigen heterogeneity, an immunosuppressive tumor microenvironment, on-target off-tumor toxicity, among other factors. To address these limitations, combinatorial approaches, such as immune checkpoint inhibitors, cytokines, and advanced gene-editing tools like CRISPR/Cas9, are being actively explored. These strategies aim to enhance CAR-T cell specificity, improve resistance to immunosuppressive signals, and optimize in vivo functionality. This review summarizes ACT approaches for CRC, with a focus on CAR-T therapy. It briefly introduces TILs and TCR-T cells, while emphasizing the major challenges faced by CAR-T therapy in solid tumors and discusses potential strategies to improve therapeutic outcomes.