靶向 P4HA1 促进 CD8(+) T 细胞祖细胞向免疫记忆和系统性抗肿瘤免疫的扩增

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 -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.