For decades, cancer immunotherapy has focused primarily on CD8+ cytotoxic T lymphocytes as the main executors of tumor cell killing. However, growing clinical and single-cell sequencing evidence shows that CD4+ T cells are far more than immune “helpers.” Within tumors, CD4+ T cell subsets exhibit remarkable heterogeneity, ranging from cytotoxic CD4+ CTLs to immunosuppressive regulatory T cells (Tregs). At the same time, chronic antigen exposure in the tumor microenvironment drives functional exhaustion, limiting therapeutic efficacy. The mechanisms underlying this duality—particularly how differentiation, metabolism, and inhibitory signaling interact—remain incompletely understood. Based on these challenges, there is an urgent need for in-depth…