CBX3 (chr7 3) is a heterochromatin protein that functions as an epigenetic regulator recognizing histone H3 methylated at lysine-9 (H3K9me3) and histone H1.4 methylated at lysine-26, leading to transcriptional repression 1. CBX3 contributes to heterochromatin formation and kinetochore assembly through interactions with chr7-modifying complexes 2. Beyond canonical chr7 binding, CBX3 binds histone acetyltransferase EP300 to modulate substrate specificity toward lactyl-CoA, driving immunosuppressive gene expression in glioblastoma 3. CBX3 also regulates DNA replication fork dynamics by binding RPA2, with phosphorylation by CK2 kinase controlling replication restart 4. Additionally, lactylation of CBX3 at lysine-10 enhances its interaction with H3K9me3, facilitating gastrointestinal cancer progression 5. Clinically, elevated CBX3 expression correlates with poor prognosis across multiple cancers, including significantly worse overall survival (HR=1.95) 6. CBX3 promotes multidrug resistance in colorectal cancer by suppressing ferroptosis through the CUL3/NRF2/GPX2 axis 7. In prostate cancer, CBX3 is upregulated by BRD4 and modulates CDK4/6 inhibitor sensitivity through RB1-E2F1 interactions 8. These findings establish CBX3 as a multifunctional epigenetic regulator contributing to cancer progression, therapeutic resistance, and immune evasion.