Stem-like CD4+ T cells mediate T-cell state transitions to enhance tumor control and immunotherapy response.

The recent breakthrough in immunotherapy has emphasized the importance of stem-like CD4+ T cells as the cornerstone to impose anti-tumor immunity. Such self-renewing T cells mature into multiple distinct effector states, which are capable of maintaining long-term immune responses in tumors. Exhibiting distinctive surface proteins and transcriptional phenotypes, they enable T-cell transitions to maintain tumor control. This review covers their phenotypic and functional characteristics, state transition mechanisms, and interaction within the tumor microenvironment. We examine how tumor-reactive stem-like CD4+ T cells cause tumor regression, with particular focus on checkpoint inhibitors and CAR-T cell therapy, while addressing the prevention of immune resistance relapse and challenges to clinical translation. This review integrates novel evidence, signaling pathways, and potential interventions to highlight the pivotal role of stem-like CD4+ T cells in cancer immunotherapy.