Unraveling the conundrum of multifaceted pyruvate kinase M2 in cancer: a potential therapeutic target with challenges in precision intervention.

Pyruvate kinase M2 (PKM2), a key glycolytic enzyme, plays a pivotal role in cancer-associated metabolic reprogramming and is frequently over-expressed in several malignancies. Beyond its metabolic activities, PKM2 exhibits numerous non-metabolic functions, mediated through a complex interplay of allosteric regulation, post-translational modifications and macromolecular interactions. Cancer cells exploit these distinctive properties to sustain Warburg effect, supporting proliferation, survival and tumor progression, making PKM2 a potential therapeutic target. Different strategies have been employed to modulate PKM2 activity in cancer (stabilizing tetrameric ensemble or mitigating its dimeric form); however, only a limited number of modulators have advanced successfully to clinical trials. This review summarizes multifaceted role of PKM2 beyond its cytoplasmic and nuclear functions, including its emerging role in exosomes, mitochondria and as RNA binding protein in tumorigenesis. Additionally, it discusses cancer-associated PKM2 mutations and their impact on structure and function. It highlights current therapeutic approaches targeting PKM2, including small-molecule modulators, as well as alternative strategies, such as antisense oligonucleotides, peptides disrupting PKM2-associated macromolecular interactions, and allosteric converters. Finally, it addresses major challenges and limitations in targeting PKM2, its context-dependent functional plasticity across cancer hallmarks, and emphasizes how deeper understanding of its structure-function dynamics may facilitate the development of more effective cancer therapeutics.