Tumor progression is strongly influenced by interactions between cancer cells and the tumor microenvironment (TME). Increasing evidence indicates that metabolic enzymes can perform functions beyond metabolism and participate in immune regulation. Pyruvate kinase M2 (PKM2), a glycolytic enzyme frequently upregulated in tumors, has been extensively studied for its intracellular roles in cancer metabolism and gene regulation. Recent studies have reported the presence of extracellular PKM2 (EcPKM2) in the circulation and extracellular matrix of cancer patients; however, its role in macrophage polarization and immune regulation remains incompletely understood. In addition, macrophage imbalance contributes to the pathogenesis of ulcerative colitis (UC), where excessive pro-inflammatory M1 macrophages promote tissue damage, while anti-inflammatory M2 macrophages facilitate tissue repair. To investigate the immunomodulatory function of EcPKM2, a recombinant PKM2 mutant (G415R) was administered in murine models of breast cancer and DSS-induced colitis. In the cancer model, 4T1 cells were orthotopically implanted into mice, and macrophage responses were examined using RAW 264.7 cells and primary bone marrow-derived macrophages. In the colitis model, mice received 2% dextran sulfate sodium (DSS), and the effects of G415R on intestinal inflammation were evaluated using macrophages and primary colonic epithelial cells. In 4T1 tumor-bearing mice, G415R treatment promoted tumor growth and lung metastasis and increased the expression of M2 macrophage markers. These effects were abolished by PKM2 antibody treatment. Mechanistically, G415R induced macrophage polarization toward the M2 phenotype through interaction with integrin αvβ3, leading to activation of the FAK–PI3K signaling pathway and suppression of PTEN expression. Knockdown of integrin β3 or overexpression of PTEN reversed this effect. In contrast, in DSS-induced colitis, G415R reduced intestinal inflammation and tissue injury. The protective effect was associated with enhanced M2 polarization, reduced epithelial apoptosis, and increased epithelial proliferation, resulting in improved mucosal repair without excessive collagen deposition. Collectively, these findings identify EcPKM2 as a regulator of macrophage polarization and immune responses. EcPKM2 promotes tumor progression by driving macrophages toward an M2 phenotype, while exerting anti-inflammatory and tissue-protective effects in colitis. This dual role highlights EcPKM2 as a potential therapeutic target in both cancer and inflammatory bowel disease.