HK3 (hexokinase 3) catalyzes the phosphorylation of glucose and fructose to their 6-phosphate derivatives, mediating the initial step of glycolysis 1. Beyond its canonical metabolic role, HK3 has emerged as a critical regulator in tumor immunology and inflammation. In clear cell renal cell carcinoma, HK3 promotes PD-L1 expression through O-GlcNAcylation of EP300, facilitating immune evasion and tumor progression 2. In cervical cancer, HK3 expression in tumor-associated macrophages (TAMs) impairs antigen cross-presentation by interacting with mTOR and promoting lysosomal degradation; HK3 inhibition restores CD8+ T-cell immunity and synergizes with checkpoint blockade 3. Similarly, in neuroblastoma, HK3 overexpression recruits and polarizes M2-like macrophages through the PI3K/AKT-CXCL14 axis, promoting tumor progression 4. In rheumatoid arthritis, senescent macrophages upregulate HK3, driving IL-17 signaling and inflammatory macrophage polarization that promotes synovial fibroblast invasion 5. Additionally, HK3 variants associate with premature ovarian failure 6. These findings position HK3 as a multifunctional therapeutic target bridging glucose metabolism with immune regulation across multiple malignancies and inflammatory diseases.