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

Abstract

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.

Keywords: CAR T cells; P4HA1; PD-1; T cell exhaustion; T cell memory; cancer immunotherapy; hypoxia; mitochondria; solid tumors; systemic immunity.