Phosphofructokinase，muscle type（PFKM）is a key rate-limiting enzyme in the glycolytic pathway，and its expression and activity are regulated by multiple signaling pathways，including hypoxia-inducible factor-1 alpha（HIF-1α），myelocytomatosis oncogene （Myc），phosphoinositide 3-kinase/protein kinase B（PI3K/AKT），and adenosine 5′ -monophosphate（AMP）-activated protein kinase （AMPK）. Recent studies have demonstrated that PFKM reprograms macrophage functions through both the canonical glycolytic pathway and“non-canonical”functions. Physicochemical factors in the microenvironment，including mechanical forces，glucose，and citrate，can shift the equilibrium between the tetrameric and dimeric conformations of PFKM，thereby facilitating the switch between its classical and non - classical functions. While current research has largely focused on the classical glycolytic role of PFKM，its non - canonical functions and the underlying molecular mechanisms remain to be fully elucidated. This review summarizes the classical and non-canonical roles of PFKM in macrophages，its upstream regulatory signals，and its implications in infectious diseases and cancer， aiming to provide a theoretical foundation and insights for PFKM-targeted immunometabolic therapeutic strategies.