The role of CD4⁺ T cells in colorectal tumors and research progress on targeting CD4⁺ T cells for antitumor strategies

CD4⁺ T cells exert dual regulatory roles in the colorectal cancer (CRC) immune microenvironment, capable of promoting anti-tumor immunity while also contributing to immunosuppression, making them critical determinants of immunotherapy efficacy. This review systematically summarizes the differentiation characteristics, regulatory mechanisms, and complex functions of CD4⁺ T cell subsets in CRC, including Th1, Th2, Th9, Th17, Treg, and Tfh cells. Th1 <?A3B2 pi129?>and Tfh cells promote CD8⁺ T cell and B cell functions by secreting cytokines such as IFN-γ and IL-21, thereby enhancing anti-tumor responses, which are closely associated with favorable patient prognosis and sensitivity to immune checkpoint inhibitors. In contrast, Th2, Th17, and Treg cells exhibit pro-tumor properties in specific microenvironments, such as inducing immunosuppression, promoting angiogenesis, and facilitating epithelial-mesenchymal transition, correlating with immune resistance in microsatellite stable (MSS) CRC patients. This review further summarizes the mechanisms and clinical application progress of CD4⁺ T cells in immune checkpoint blockade, cancer vaccines, and CAR-T cell therapy. For instance, the combination of nivolumab and ipilimumab has shown significant efficacy in MSI-H CRC; personalized neoantigen vaccines and mRNA vaccines demonstrate the potential to activate the helper functions of CD4⁺ T cells; in CAR-T cell therapy, CD4⁺ T cells can enhance therapeutic efficacy and prolong the duration of immune responses. Despite important advances, challenges remain, including the limited response of MSS CRC to immunotherapy, the high heterogeneity of CD4⁺ T cells, and the need to balance safety and efficacy in combination therapies. Future research should focus on precisely regulating CD4⁺ T cell differentiation, reversing immune resistance, optimizing engineered T cell design, and strengthening clinical translational studies, so as to achieve the transition from ″understanding the microenvironment″ to ″remodeling the microenvironment", ultimately providing more effective immunotherapy strategies for CRC patients. <alternatives id="alt2"> </alternatives>