Pyruvate kinase M2 (PKM2) is a central regulator of cancer metabolism, bridging metabolic reprogramming with oncogenic signaling and immune modulation. Unlike constitutively active PKM1, PKM2 displays structural and functional plasticity, allowing dynamic control of glycolytic flux while supporting anabolic processes associated with the Warburg effect. Beyond metabolism, PKM2 translocates to the nucleus, where it acts as a transcriptional coactivator and protein kinase influencing proliferation, angiogenesis, metastasis, redox balance, epigenetic remodeling, and therapeutic resistance. This review summarizes current knowledge on PKM2 as an immunometabolic regulator within the tumor microenvironment, focusing on immune cell polarization, metabolic competition, and immune evasion. It also discusses therapeutic strategies, including splice-switching antisense oligonucleotides, small-molecule inhibitors and activators, and antibody-based approaches targeting intracellular or extracellular PKM2. Although PKM2-directed therapies may enhance immunotherapy, challenges such as metabolic adaptability, isoform compensation, limited biomarkers, and scarce clinical data remain significant barriers to translation.
Grzelecka et al. (Thu,) studied this question.
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