Post-translational modifications in CD8+ T cell exhaustion: mechanisms, networks, and epigenetic locking.

CD8+ T cells are core effector cells of adaptive immunity. However, in chronic infection and tumor microenvironments, they often lose their effector functions. Under persistent antigenic and metabolic stress, CD8+ T cells may progressively acquire a stable dysfunctional state termed T cell exhaustion. Post-translational modifications (PTMs) constitute a rapid and dynamic regulatory system that targets four core functional modules: membrane receptor signaling, transcription factors, metabolic enzymes, and epigenetic regulators. These modules are interconnected through a multi-layered PTM network. Within this network, PTMs orchestrate a stepwise cascade that proceeds from signal initiation through metabolic reprogramming to transcriptional and epigenetic remodeling. Ultimately, this cascade consolidates the exhaustion program via stable epigenetic memory. Accordingly, we propose a "PTM-driven signal-metabolism-epigenetic locking model" as the central framework of this review. Focusing on five key PTMs, namely phosphorylation, ubiquitination, glycosylation, acetylation, and lactylation, we elucidate how these modifications cooperatively regulate CD8+ T cell exhaustion. Critically, the PTM network drives progressive locking of the exhausted state through three epigenetic layers: DNA methylation, chromatin remodeling, and histone modifications. These layers collectively contribute to the progressive stabilization of the exhausted state over time. This framework integrates transient environmental signals, metabolic fluctuations, and transcriptional changes into permanent cell fate decisions. Building upon this mechanistic understanding, the review further explores novel strategies targeting the PTM network to reverse exhaustion and enhance immunotherapeutic efficacy. This review provides a clear and comprehensive framework for understanding how PTMs govern CD8+ T cell exhaustion and lays a solid foundation for the development of next-generation immunotherapies.