PTMA Safeguards Mitochondrial Integrity to Sustain Metabolic Function and Antitumor Persistence of CD8+ T Cells

While immune checkpoint blockade (ICB) has revolutionized cancer treatment, its clinical efficacy remains constrained by the progressive exhaustion of tumor-reactive CD8+ T cells - a dysfunctional state intimately linked to mitochondrial impairment. This underscores the urgent need to identify and target molecular regulators that govern mitochondrial metabolic fitness in CD8+ T cells, thereby preserving their effector function within the immunosuppressive tumor microenvironment (TME) to improve therapeutic outcomes. Through integrative single-cell TCR-seq and longitudinal transcriptomic profiling of reactive CD8+ T cell clones during clinical ICB treatment, we found PTMA levels in CD8+ T cells showed significant positive correlation with clinical ICB efficacy, establishing its potential as a predictive biomarker for immunotherapy outcomes. Importantly, we demostrated that Ptma expression is directly regulated by T cell factor 1 (TCF1), a transcription factor essential for T cell stemness. Moreover, genetic ablation of Ptma severely compromises the persistent effector function of CD8+ T cells and completely abrogates the in vivo efficacy of ICB. Mechanistically, we reveal that PTMA physically interacts with TFAM to safeguard mitochondrial DNA (mtDNA) integrity in CD8+ T cells under metabolic stress, thereby maintaining electron transport chain (ETC) function and oxidative phosphorylation (OXPHOS) capacity. Collectively, our findings delineate the TCF1-PTMA axis as a critical molecular nexus connecting mitochondrial metabolic competence to the stem-like properties of CD8+ T cells. This discovery provides both fundamental insights into the metabolic regulation of antitumor immunity and clinically actionable strategies to overcome ICB resistance. Overall design: A comparative RNA-seq analysis of wild-type versus PTMA-overexpressing OT1 CD8+ T cells under 48-hour OVA peptide stimulation