Beyond tumor cell–intrinsic metabolism: Hexokinase 2 as a central regulator of the tumor microenvironment

Hexokinase 2 (HK2), a mitochondrial-bound glycolytic rate-limiting enzyme, is frequently overexpressed in cancers and tightly regulated at multiple levels. Beyond driving the Warburg effect, HK2 suppresses multiple forms of programmed cell death, including apoptosis, pyroptosis, and ferroptosis. Emerging evidence further identifies HK2 as a key regulator of the tumor microenvironment, where it shapes the metabolic programming and function of cancer stem cells, macrophages, dendritic cells, and T cells, and forms a bidirectional regulatory loop with PD-L1 to facilitate immune evasion. Various HK2-targeting approaches—including small molecules, natural compounds, and PROTACs—have been developed, with nano-formulated PROTACs showing improved selectivity and tumor targeting. This review highlights the emerging non-canonical roles of HK2 in the tumor microenvironment and discusses strategies to translate these insights into effective clinical interventions.