PFKP in malignant tumors: bridging metabolic reprogramming, post-translational modifications, and the immunosuppressive microenvironment.

Abstract

Metabolic reprogramming is a hallmark of malignant tumors. Platelet-type phosphofructokinase (PFKP), a rate-limiting enzyme in glycolysis, is aberrantly overexpressed across diverse cancers and promotes tumor proliferation, invasion, and metastasis through both metabolic and non-metabolic pathways. The enzymatic activity, stability, and subcellular localization of PFKP are dynamically regulated by post-translational modifications-including phosphorylation, ubiquitination, acetylation, and lactylation-as well as by protein-protein interaction networks. Upon nuclear translocation, PFKP dissociates from glycolytic flux and engages in oncogenic transcriptional regulation. Moreover, PFKP upregulates PD-L1 expression, alters chemokine profiles, disrupts immune cell infiltration, and fosters an immunosuppressive microenvironment that facilitates immune evasion. Emerging evidence suggests PFKP holds diagnostic and prognostic potential, yet direct targeting evidence remains lacking, and most inhibitor studies are confined to preclinical models. This review synthesizes recent advances in PFKP research, focusing on its regulatory networks in tumor metabolism, post-translational modifications, protein interactions, and immune remodeling. We critically evaluate current controversies, unresolved questions, and translational barriers, and propose future directions-including epigenetic regulation, functional characterization of interacting partners, and combination strategies with immunotherapy-to inform precision oncology and targeted therapeutic development.