Platelet-Type Phosphofructokinase Drives Immune Checkpoint Coexpression and Metabolic Pathway Activation in Liver...

Hepatocellular carcinoma (HCC) is associated with poor clinical outcomes, underscoring the need to identify novel biomarkers and therapeutic targets. Platelet-type phosphofructokinase (PFKP), a key rate-limiting enzyme in glycolysis, is involved in tumor metabolic reprogramming, but its role in HCC prognosis, immune regulation, and therapeutic responsiveness remains incompletely understood.

We combined transcriptomic profiles and clinical information from The Cancer Genome Atlas with analyses of clinical HCC specimens. PFKP expression, survival associations, functional enrichment, and tumor immune microenvironment characteristics were systematically evaluated. Drug sensitivity was predicted using data from the Genomics of Drug Sensitivity in Cancer database. Validation was performed by immunohistochemistry in patient samples and by Western blotting in PFKP-overexpressing HepG2 cells treated with or without the glycolysis inhibitor 2-deoxy- d -glucose.

PFKP expression was markedly increased in HCC and was independently associated with unfavorable survival. Elevated PFKP levels were linked to an immunoregulatory microenvironment and increased expression of immune checkpoint molecules (PD-L1, CTLA-4), which was confirmed by immunohistochemistry. High PFKP expression was also associated with predicted greater responsiveness to immune checkpoint blockade and distinct drug sensitivity profiles. Mechanistically, PFKP overexpression increased the expression of key glycolytic enzymes, enhanced PD-L1 expression, and was accompanied by activation of mechanistic target of rapamycin (mTOR)-related signaling, whereas these effects were attenuated by glycolytic inhibition.

PFKP is a critical link between glycolysis and immune suppression in HCC. It promotes immune checkpoint expression and mTOR activation, suggesting a role in immune evasion. PFKP represents a dual biomarker for prognosis and immunotherapy response, and a promising target for combined metabolic and immune-based therapies.