Abstract: Metabolic reprogramming is a defining feature of cancer that facilitates unregulated proliferation, adaptation to stress, and therapeutic resistance. Pyruvate kinase M2 (PKM2), a crucial glycolytic isoform, links cancer-causing signaling pathways to metabolic control and has become both a biomarker and a therapeutic target. In addition to its catalytic role, PKM2 regulates gene expression, immune evasion, and hypoxia adaptation, placing it at the intersection of multiple cancer hallmarks. This review integrates structural, biochemical, and functional evidence to analyze PKM2's involvement in tumor proliferation, therapeutic resistance, and its modulation by both natural and synthetic agents, including shikonin and metformin. Preclinical studies show that targeting PKM2 can reduce glycolytic flux, make tumor cells more sensitive to chemotherapy, and slow tumor growth. Nonetheless, clinical translation remains difficult due to resistance mechanisms, limited selectivity, off-target effects, low bioavailability, and expression in normal proliferating tissues. Recent advancements in multi-omics profiling and drug design offer opportunities to overcome these obstacles through more selective modulators, biomarkerdriven patient stratification, and rational combination therapies. This review critically assesses the potential and constraints of PKM2, highlighting translational challenges and future research priorities to establish PKM2 as a clinically significant target in precision oncology.
Kumar et al. (Thu,) studied this question.