Regulation of T cell exhaustion and stemness: molecular mechanisms and implications for cancer immunotherapy

T cells are central components of the adaptive immune system and play key roles in antitumor and antiviral responses. The diverse cell fates of T cells enable them to respond to different durations and strengths of antigen stimulation and various cytokine milieus in a context-dependent manner. During acute infection or vaccination, T cells differentiate into effector cells and later develop into memory cells after antigen clearance, which mediate immune protection against the same antigen. In contrast, during cancer and chronic infection, T cells fail to enter the canonical effector or memory cell differentiation path. Instead, antigen-specific T cells enter a dysfunctional, partially responsive state called exhaustion. Exhausted T cells are heterogeneous. A subset of exhausted T cells exhibits stem cell-like properties. These stem-like T cells sustain immunity through self-renewal and repopulation of terminally differentiated progenies. Stem-like properties are critical for T cell immunity induced by immunotherapy. This review summarizes recent advances in understanding the molecular mechanisms controlling the exhaustion and stemness of T cells and explores the potential of rewiring these circuits to increase the efficiency of T-cell-based immunotherapy.