CD4+ T cells in cancer: dual roles, exhaustion, and therapeutic breakthroughs

In recent years the crucial role of CD4⁺ T cells in tumor immunomodulation has garnered increasing recognition. While conventional cancer immunotherapy research has predominantly focused on the cytotoxic function of CD8⁺ T cells, emerging evidence has now shown that CD4⁺ T cells enhance antitumor immunity by delivering co-stimulatory signals, secreting cytokines, and promoting cytotoxic T lymphocyte (CTL) activation and display unique immunoregulatory capabilities through direct tumor cell killing or remodeling of the tumor microenvironment. The high heterogeneity and functional plasticity of CD4⁺ T cell subsets significantly influence clinical responses to immunotherapy with underlying mechanisms involving multi-level regulatory networks, including epigenetic modulation and metabolic reprogramming. Deciphering the functional heterogeneity of CD4⁺ T cells and the interactions with the tumor microenvironment will provide essential mechanistic insights for next-generation immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) therapies, thereby advancing personalized treatment paradigms.