TGM2-mediated serotonylation in tumor endothelial cells promotes angiogenesis and tumor growth in colorectal cancer.

Angiogenesis fuels colorectal cancer (CRC) growth and metastasis by supplying oxygen and nutrients to expanding tumors. Here, we define a TGM2-mediated serotonylation axis in tumor endothelial cells as a driver of angiogenesis and a key mediator of epigenetic reprogramming within the tumor microenvironment. Across CRC single-cell datasets, TGM2 is broadly expressed in endothelial cells, and endothelial TGM2 correlates with the H3Q5Ser mark. Endothelial-specific deletion of Tgm2 in mice markedly suppresses angiogenesis and slows allograft tumor growth. In human umbilical vein endothelial cells, TGM2 knockdown diminishes H3Q5Ser, proliferation, migration, and tube formation, which can be rescued with nuclear-localized wild-type TGM2 but not a transamidase-inactive mutant. Mechanistically, TGM2-catalyzed serotonylation promotes LDHA transcription via H3Q5Ser at the LDHA promoter, thereby upregulating glycolysis. Hypoxia induces TGM2 expression via HIF-1α signaling. Moreover, endothelial cells lack canonical serotonin transporters and serotonin biosynthesis, and exosome-mediated transfer of 5-HT provides a source that fuels endothelial serotonylation. Clinically, high endothelial TGM2 and H3Q5Ser levels predict poorer prognosis. Collectively, the TGM2-serotonylation axis in endothelial cells represents a promising therapeutic target to disrupt tumor angiogenesis and CRC progression, with potential to synergize with immunotherapy by normalizing tumor vasculature and enhancing anti-tumor immunity.