HK3 encodes hexokinase 3, an enzyme that catalyzes the phosphorylation of hexose sugars (glucose and fructose) to their 6-phosphate forms, mediating the initial committed step of glycolysis. Beyond its classical role in glucose metabolism, HK3 has emerged as a critical regulator of immune suppression and tumor progression across multiple cancer types. In clear cell renal cell carcinoma (ccRCC), HK3 promotes O-GlcNAcylation of the coactivator EP300 at serine 900, enhancing its stability and enabling it to drive PD-L1 transcription—a key immune checkpoint ligand 1. In cervical cancer, HK3 expression in tumor-associated macrophages (TAMs) impairs antigen cross-presentation by physically interacting with mTOR and promoting TFEB-mediated excessive lysosomal activation; HK3 inhibition restores CD8+ T-cell-mediated antitumor immunity and synergizes with immune checkpoint blockade 2. Similarly, in neuroblastoma, HK3 overexpression correlates with poor prognosis and M2-like TAM infiltration, where it recruits and polarizes immunosuppressive macrophages through the PI3K/AKT-CXCL14 axis 3. In oesophageal squamous cell carcinoma, HK3 protein deficiency combined with creatine accumulation drives immunosuppressive M2-like TAM polarization 4. A 2024 study in rheumatoid arthritis identifies HK3 upregulation in senescent macrophages as a driver of IL-17-mediated inflammation, with HK3 knockdown reducing lactate secretion and histone lactylation 5. Additionally, genetic evidence links HK3 variants to both age at natural menopause and premature ovarian failure 6. These findings establish HK3 as a dual-function biomarker and therapeutic target bridging glucose metabolism to immune evasion and inflammatory disease.