Post‐Translational Regulation of CD8 ⁺ T Cell Fate and Dysfunction in Tumor Immunity

ABSTRACT CD8 ⁺ T cells are central executors of antitumor immunity, yet their activation, effector differentiation, and long‐term persistence are governed by diverse post‐translational modifications (PTMs). These chemical modifications function as rapid and reversible regulators that link antigenic stimulation, metabolic availability, and inflammatory cues to the transcriptional and chromatin programs that define CD8 ⁺ T cell fate. Core PTM classes—including phosphorylation, ubiquitination, acetylation, methylation, and glycosylation—precisely tune signaling thresholds, cytotoxic commitment, and memory formation, while emerging metabolism‐responsive modifications such as lactylation directly connect nutrient flux to functional fitness. In solid tumors, chronic antigen exposure, hypoxia, nutrient restriction, and lactate accumulation profoundly remodel these modification networks, stabilizing dysfunction‐associated states, impairing metabolic flexibility, and diminishing cytotoxic capacity. This review integrates current mechanistic understanding of how major PTM pathways coordinate the lifecycle of CD8 ⁺ T cells—from initial activation to effector acquisition, memory establishment, dysfunction, and exhaustion. We further discuss how the tumor microenvironment reprograms PTM landscapes to reinforce dysfunction and promote immune escape. Finally, we highlight the challenges and future directions in deciphering and targeting PTMs in CD8 ⁺ T cells. Future efforts to manipulate PTMs hold significant potential to improve cancer immunotherapies by restoring the antitumor efficacy of CD8 ⁺ T cells within the tumor microenvironment.