Targeting P4HA1 promotes CD8+ T cell progenitor expansion toward immune memory and systemic anti-tumor immunity

Successful immunotherapy relies on both intratumoral and systemic immunity, which is yet to be achieved for most patients with cancer. Here, we identify P4HA1, encoding prolyl 4-hydroxylase 1, as a crucial regulator of CD8+ T cell differentiation strongly upregulated in tumor-draining lymph nodes (TDLNs) and hypoxic tumor microenvironment. P4HA1 accumulates in mitochondria, disrupting the tricarboxylic acid (TCA) cycle through aberrant α-ketoglutarate and succinate metabolism, promoting mitochondria unfitness and exhaustion while suppressing progenitor expansion. Targeting P4HA1 enhances both adoptive and endogenous TCF1+ CD8+ T progenitor expansion while mitigating the development of exhaustion in the tumor, TDLN, and blood, enabling a notable and durable systemic anti-cancer immunity. We propose that P4HA1 induction in CD8+ T cells in cancer orchestrates an immune-escape program, offering a T cell-directed target for system immunotherapy in solid tumors. [Display omitted] •P4HA1 is upregulated in CD8+ T cells upon activation and exhaustion•P4HA1 induces mitochondrial dysfunction and T cell exhaustion by disrupting TCA cycle•Targeting P4HA1 expands progenitor CD8+ T cells, enabling systemic anti-cancer immunity•P4HA1+ CD8+ T subset is a biomarker for cancer progression and immune monitoring Ma et al. identify P4HA1 as a critical regulator of CD8+ T cell activity in solid tumor microenvironment. P4HA1 induction in CD8+ T cells causes mitochondrial dysfunction and immune exhaustion. P4HA1 inhibition enhances the progenitor CD8+ T cell expansion while mitigating exhaustion, leading to enhanced systemic anti-tumor immunity.