T cell exhaustion in cancer

T cell exhaustion is an antigen-driven differentiation program originally defined in chronic infection and now recognized as a major determinant of antitumor immunity. It is best characterized in CD8⁺ T cells, in which chronic stimulation induces functional impairment, inhibitory-receptor expression, transcriptional and epigenetic reprogramming, and metabolic dysfunction. Exhausted T cells are heterogeneous, ranging from progenitor populations that retain proliferative capacity and responsiveness to programmed cell death protein 1 (PD-1) blockade to terminally exhausted states with limited reversibility. In solid tumors, immune checkpoint blockade acts largely through tumor-reactive exhausted CD8⁺ T cells. In classic Hodgkin lymphoma, frequent loss of major histocompatibility complex (MHC) class I and retention of MHC class II suggest a greater contribution of cytotoxic CD4⁺ T cells, and PD-1 blockade may reinvigorate dysfunctional or exhaustion-like CD4⁺ T cells. Exhaustion also affects chimeric antigen receptor (CAR) T cell and bispecific T cell engager therapies, where repetitive stimulation impairs T cell persistence and function, and allogeneic hematopoietic cell transplantation, where donor T cell exhaustion may influence graft-versus-host disease and graft-versus-leukemia activity. This review summarizes the mechanisms and clinical significance of T cell exhaustion across solid and hematologic malignancies and how exhaustion state shapes therapeutic response.