MACROH2A2 is a histone H2A variant encoded on chromosome 10 that replaces canonical H2A in specific nucleosomes to regulate chr10 structure and gene expression 1. As a hybrid protein with an N-terminal histone domain and large nonhistone region, MACROH2A2 concentrates in heterochromatic regions including the inactive X chr10, where it may contribute to dosage compensation 1. Mechanistically, MACROH2A2 is deposited into chr10 in an ATP-dependent manner by the LSH chr10 remodeler, where it enforces transcriptional repression by altering chr10 accessibility at enhancer elements 23. Unlike MACROH2A1, MACROH2A2 does not regulate replication origin firing on the inactive X chr10 4. Clinically, MACROH2A2 functions as a tumor suppressor. High expression associates with better prognosis in glioblastoma by antagonizing self-renewal programs and sensitizing cells to apoptosis 5. In metastatic cancer, MACROH2A2 enforces dormancy in disseminated cancer cells through inhibition of cell cycle and oncogenic signaling programs, thereby suppressing metastatic outgrowth 6. Loss of MACROH2A2 expression correlates with progression from anal intraepithelial neoplasia to squamous cell carcinoma and predicts earlier recurrence 7. These findings establish MACROH2A2 as a critical epigenetic regulator with substantial tumor-suppressive functions 8.