Multiverse of phosphorglycerate kinase: Exploring canonical, moonlighting, and tumor microenvironmental functions

The phosphoglycerate kinase family includes PGK1 and PGK2, which are traditionally characterized as typical glycolytic enzymes responsible for catalyzing the generation of ATP during glucose metabolism. However, accumulating evidence has uncovered a broad array of non-canonical, non-enzymatic “moonlighting” functions associated with these proteins. Beyond their metabolic roles, PGK1 and PGK2 are increasingly recognized as multifunctional regulators in cancer biology—modulating intracellular signaling pathways, remodeling the extracellular matrix, shaping immune responses, and promoting metastasis. Notably, their functions are context-dependent and spatially organized within the tumor microenvironment (TME), where they may act as adaptive stress sensors and immune response sculptors. While previous studies have primarily focused on transcriptional regulation and enzymatic kinetics, this review provides a thorough reevaluation of PGK's moonlighting functions in tumor progression and the TME. We highlight emerging evidence supporting their involvement in extracellular signaling, stress adaptation, and immune evasion, while also integrating various novel post-translational modifications of PGKs. This perspective may offer novel therapeutic avenues by targeting their non-enzymatic, cancer-promoting activities.