Inhibiting P4HA1 for antitumor immunity

Inhibiting CD8⁺ T cell P4HA1 — an a-ketoglutarate-dependent metabolic enzyme that accumulates in mitochondria, where it disrupts the Krebs cycle and promotes mitochondrial dysfunction and subsequent immune exhaustion — could help treat hypoxic solid tumors by increasing expansion of progenitor stem-like CD8⁺ T cells that drive antitumor immunity.

RNA-sequencing of EGFR CAR T cells generated from healthy donor peripheral blood mononuclear cells and co-cultured with an EGFR-expressing human colorectal cancer cell line identified P4HA1 as the most increased gene in CD8⁺ T cells that were activated early and exhausted. ...