Balancing Intrinsic and Extrinsic Factors in CD8+ T Cell Therapy.

Persistent Ag exposure in tumors, chronic infections, and autoimmune diseases progressively drive CD8+ T cell dysfunction-a process known as T cell exhaustion. During this process, progenitor exhausted CD8+ T (Tpex) cells represent an early subset with stem cell-like properties and serve as key mediators of immune checkpoint blockade responses. Despite their longevity and proliferative capacity, Tpex cells display limited cytotoxicity. Upon sustained TCR stimulation, they differentiate into exhausted CD8+ T (Tex) cells that express high levels of granzyme B and contribute critically to tumor elimination. Accumulating evidence indicates that Tex cells are functionally heterogeneous, as defined by diverse surface markers and transcriptional programs, and their states are further shaped by tissue- and context-specific cues within the tumor or inflammatory microenvironment. Such extrinsic signals can compromise CD8+ T cell function and limit the efficacy of anti-PD-1 therapy. A comprehensive understanding of this heterogeneity, integrating both intrinsic transcriptional regulation and extrinsic modulatory signals, is crucial for developing more effective immunotherapeutic strategies. Finally, T cell exhaustion should not be viewed solely as a pathological endpoint but also as an adaptive mechanism that restrains immunopathology, underscoring its context-dependent roles across cancer, infection, and autoimmunity.