PCK1 inhibits cGAS-STING activation by consumption of GTP to promote tumor immune evasion

Area of Science:

• Immunology
• Metabolic pathways
• Cancer research

Background:

• Hypoxia promotes tumor immune evasion by suppressing cytosolic DNA-sensing pathways like cGAS-STING.
• The precise mechanisms by which tumor cells achieve this immune suppression under hypoxia are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms linking hypoxia, metabolic enzymes, and the cGAS-STING pathway in tumor immune evasion.
• To investigate the therapeutic potential of targeting this newly identified pathway in cancer treatment.

Main Methods:

• Investigated hypoxia-induced signaling in tumor cells.
• Utilized biochemical assays to study protein-protein interactions and enzyme kinetics (PCK1 and cGAS).
• Employed mouse models of cancer and analyzed human breast cancer specimens.

Main Results:

• Hypoxia induces JNK1/2-mediated phosphorylation of PCK1 at S151, promoting its interaction with cGAS.
• Phosphorylated PCK1 competitively consumes GTP, inhibiting cGAS activation and downstream STING signaling.
• PCK1 inhibition, combined with anti-PD-1 therapy, significantly reduced tumor growth in mice.
• PCK1 S151 phosphorylation inversely correlates with cGAS-STING activation and patient survival in breast cancer.

Conclusions:

• PCK1 acts as a metabolic regulator that suppresses the cGAS-STING innate immune pathway in hypoxic tumors.
• Targeting PCK1 phosphorylation offers a novel strategy to overcome tumor immune evasion and enhance immunotherapy efficacy.
• This study highlights the critical role of metabolic reprogramming in controlling anti-tumor immunity.