HKDC1 (hexokinase domain containing 1) is a glucose phosphorylating enzyme with low catalytic activity compared to other hexokinases 1. Beyond canonical glucose metabolism, HKDC1 functions as a glucose sensor that modulates its stability in response to environmental glucose availability, enabling metabolic adaptation to glucose starvation by promoting mitochondrial fatty acid utilization 2. Mechanistically, HKDC1 exerts pleiotropic effects in cancer through multiple pathways. In hepatocellular carcinoma (HCC), HKDC1 promotes liver cancer stemness under hypoxia by stabilizing β-catenin through glycogen synthase kinase 3β interaction 3. HKDC1 facilitates immune evasion by coupling cytoskeleton protein ACTA2 to STAT1 activation and subsequent PD-L1 expression on tumor cells 4. In gastric cancer, HKDC1 reprograms lipid metabolism via an HKDC1/G3BP1-PRKDC regulatory axis to enhance metastasis and chemoresistance 5. Additionally, H. pylori infection upregulates HKDC1 to activate the TGF-β/Smad2 epithelial-mesenchymal transition pathway 6. In pancreatic adenocarcinoma, HKDC1 interacts with PARP1 to enhance autophagy and cell proliferation 7. Clinically, HKDC1 overexpression associates with poor prognosis and tumor metastasis across multiple cancer types 8. HKDC1 inhibition combined with anti-PD-L1 therapy enhances antitumor immunity 4, suggesting potential therapeutic utility.