PKM2 phosphorylation by c-SRC activates glycolysis and metastasis with the stimulation of tumor-associated macrophages.

Metabolic reprogramming plays key role in the progression of malignancies. Through the remodeling of glucose metabolism, tumor cells can achieve rapid proliferation of energy supply and efficient synthesis of biomacromolecules. Pyruvate kinase M2(PKM2) is highly expressed among kinds of tumors and is thought to be vital for the phenomenon of aerobic glycolysis. Here we demonstrate that tumor-associated macrophages (TAMs) could promote glycolysis and metastasis of colon cancer. Mechanically, PKM2 is phosphorylated at Y175 by c-SRC with the stimulation of TAMs. Meanwhile, PKM2 Y175 phosphorylation facilitates PKM2 nuclear translocation and colon cancer cells progression. In clinical tumor specimen, PKM2 Y175 phosphorylation mediated by c-SRC is associated with macrophage infiltration and is predictive of poor prognosis. Collectively, our findings reveal how tumor microenvironment interferes with tumor metabolic reprogramming. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-026-02766-7.