T-cell exhaustion in tumor immunology: mechanisms, heterogeneity, and therapeutic strategies

Abstract

T-cell exhaustion is a central mechanism limiting the durability of antitumor immunity and the long-term efficacy of cancer immunotherapy. Arising under persistent antigenic stimulation and sustained microenvironmental stress, exhausted CD8+ T cells undergo progressive functional impairment accompanied by stable transcriptional, epigenetic, and metabolic reprogramming. Importantly, exhaustion is now understood not as a uniform dysfunctional endpoint but as a hierarchically organized and context-dependent differentiation continuum comprising progenitor, intermediate, and terminally exhausted states with distinct degrees of plasticity and therapeutic responsiveness. This framework helps explain why immune checkpoint blockade and related therapies often produce incomplete and non-durable clinical responses, as they predominantly act on progenitor-like exhausted T cells while leaving terminally exhausted populations largely refractory to reprogramming. In this review, we integrate current knowledge of the developmental heterogeneity, molecular mechanisms, and tumor microenvironmental regulation underlying T-cell exhaustion, and examine how these features shape the efficacy of major immunotherapeutic strategies. We further suggest that future progress will depend on moving beyond attempts to globally reverse exhaustion and instead adopting state-oriented approaches that preserve progenitor-like T-cell pools, restrain terminal differentiation, and remodel the immunosuppressive tumor microenvironment.