MacroH2A在黑色素瘤和其他癌症中已经确定了抑制肿瘤的功能，但在肿瘤微环境中的作用没有得到足够的重视。使用自生的、免疫竞争的黑色素瘤小鼠模型，我们证明缺乏MacroH2A变异体的小鼠相对于野生型小鼠具有更大的肿瘤负担。缺乏MacroH2A的肿瘤堆积了免疫抑制性单核细胞，并缺乏功能性细胞毒性T细胞，这些特征与抗肿瘤应答受损一致。单细胞和空间转录组学表明，在肿瘤组织中，神经嵴系列的去分化增加，并且在MacroH2A缺失后，肿瘤相关成纤维细胞的频率和活化程度增加。从机制上讲，MacroH2A缺陷的癌相关成纤维细胞由于其促炎基因的高度诱导表达增加了造血化学引诱活性，这是通过其启动子与增强子之间增强了H3K27ac的染色质环形联系来强制实现的。总之，我们揭示了MacroH2A变异体通过调节肿瘤间质中的染色质结构发挥抑制肿瘤的作用，对人类黑色素瘤可能具有潜在的影响。© 2023.作者（们）。

MacroH2A has established tumour suppressive functions in melanoma and other cancers, but an unappreciated role in the tumour microenvironment. Using an autochthonous, immunocompetent mouse model of melanoma, we demonstrate that mice devoid of macroH2A variants exhibit increased tumour burden compared with wild-type counterparts. MacroH2A-deficient tumours accumulate immunosuppressive monocytes and are depleted of functional cytotoxic T cells, characteristics consistent with a compromised anti-tumour response. Single cell and spatial transcriptomics identify increased dedifferentiation along the neural crest lineage of the tumour compartment and increased frequency and activation of cancer-associated fibroblasts following macroH2A loss. Mechanistically, macroH2A-deficient cancer-associated fibroblasts display increased myeloid chemoattractant activity as a consequence of hyperinducible expression of inflammatory genes, which is enforced by increased chromatin looping of their promoters to enhancers that gain H3K27ac. In summary, we reveal a tumour suppressive role for macroH2A variants through the regulation of chromatin architecture in the tumour stroma with potential implications for human melanoma.© 2023. The Author(s).