癌细胞编辑基因表达以逃避免疫监视。然而，缺乏早期肿瘤发生过程中基因编辑的全基因组研究。在这里，我们在乳腺癌基因工程小鼠模型 (GEMM) 中使用单细胞 RNA 测序来无偏差地识别编辑基因。晚期肿瘤抑制抗肿瘤免疫基因，减少浸润免疫细胞和肿瘤免疫细胞通讯。先天免疫基因，尤其是干扰素刺激的基因，在下调的肿瘤基因列表中占主导地位，而调节细胞内在恶性肿瘤的基因大多未经编辑。早期肿瘤中初始和活化的 CD8 T 细胞在晚期肿瘤中被耗尽或前体耗尽的细胞所取代。通过使用低剂量地西他滨抑制 DNA 甲基化，可以逆转免疫基因的抑制，从而抑制肿瘤生长并恢复免疫控制，增加肿瘤浸润淋巴细胞的数量、功能和记忆，并减少骨髓抑制细胞的数量。地西他滨在 GEMM 以及植入性乳腺和黑色素瘤肿瘤中诱导重要的干扰素、焦亡和坏死性凋亡基因、炎症细胞死亡和免疫控制。© 2024。作者获得 Springer Nature America, Inc. 的独家许可。

Cancer cells edit gene expression to evade immunosurveillance. However, genome-wide studies of gene editing during early tumorigenesis are lacking. Here we used single-cell RNA sequencing in a breast cancer genetically engineered mouse model (GEMM) to identify edited genes without bias. Late tumors repressed antitumor immunity genes, reducing infiltrating immune cells and tumor-immune cell communications. Innate immune genes, especially interferon-stimulated genes, dominated the list of downregulated tumor genes, while genes that regulate cell-intrinsic malignancy were mostly unedited. Naive and activated CD8+ T cells in early tumors were replaced with exhausted or precursor-exhausted cells in late tumors. Repression of immune genes was reversed by inhibiting DNA methylation using low-dose decitabine, which suppressed tumor growth and restored immune control, increasing the number, functionality and memory of tumor-infiltrating lymphocytes and reducing the number of myeloid suppressor cells. Decitabine induced important interferon, pyroptosis and necroptosis genes, inflammatory cell death and immune control in GEMM and implanted breast and melanoma tumors.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.