PTMA safeguards mitochondrial integrity to sustain metabolic function and antitumor activity of CD8 T cells

Immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often limited by the progressive exhaustion of tumor-reactive CD8 T cells. By analyzing transcriptomes of CD8 T cells from patients treated with ICB across cancer types, we found that prothymosin alpha (PTMA) is highly expressed in progenitor exhausted T (T_PEX) cells and is associated with treatment response. PTMA expression was directly controlled by T cell factor 1 (TCF1), a central regulator of T_PEX cell maintenance in the tumor microenvironment. In mice, genetic deletion of <i>Ptma</i> from T cells compromised CD8 T cell persistence in tumors and abolished the therapeutic effect of programmed cell death protein 1 (PD-1) blockade. PTMA preserved mitochondrial DNA integrity through interaction with mitochondrial transcription factor A (TFAM), sustaining T cell oxidative phosphorylation under metabolic stress. Our findings identify the TCF1-PTMA axis as a molecular link between mitochondrial fitness and durable T cell-mediated antitumor immunity, offering insights and potential directions for future therapeutic strategies to boost immunotherapy efficacy.