Tumours use various strategies to evade immune surveillance^1,2. Immunotherapies targeting tumour immune evasion such as immune checkpoint blockade have shown considerable efficacy on multiple cancers^3,4 but are ineffective for most patients due to primary or acquired resistance^5,6,7. Recent studies showed that some epigenetic regulators suppress anti-tumour immunity^{2,8,9,10,11,12}, suggesting that epigenetic therapies could boost anti-tumour immune responses and overcome resistance to current immunotherapies. Here we show that, in mouse melanoma models, depletion of KDM5B—an H3K4 demethylase that is critical for melanoma maintenance and drug resistance^13,14,15—induces robust adaptive immune responses and enhances responses to immune checkpoint blockade. Mechanistically, KDM5B recruits the H3K9 methyltransferase SETDB1 to repress endogenous retroelements such as MMVL30 in a demethylase-independent manner. Derepression of these retroelements activates cytosolic RNA-sensing and DNA-sensing pathways and the subsequent type-I interferon response, leading to tumour rejection and induction of immune memory. Our results demonstrate that KDM5B suppresses anti-tumour immunity by epigenetic silencing of retroelements. We therefore reveal roles of KDM5B in heterochromatin regulation and immune evasion in melanoma, opening new paths for the development of KDM5B-targeting and SETDB1-targeting therapies to enhance tumour immunogenicity and overcome immunotherapy resistance.

肿瘤使用各种策略来逃避免疫监视^1,2。针对肿瘤免疫逃避的免疫疗法（例如免疫检查点阻断）已对多种癌症显示出相当大的疗效^3,4但由于原发性或获得性耐药性对大多数患者无效^5,6,7。最近的研究表明，一些表观遗传调节剂会抑制抗肿瘤免疫^{2,8,9,10,11,12}，这表明表观遗传疗法可以增强抗肿瘤免疫反应并克服对当前免疫疗法的耐药性。在这里，我们表明，在小鼠黑色素瘤模型中，KDM5B 的耗竭 - 一种对黑色素瘤维持和耐药性至关重要的 H3K4 去甲基化酶^13,14,15—诱导强大的适应性免疫反应并增强对免疫检查点封锁的反应。从机制上讲，KDM5B 招募 H3K9 甲基转移酶 SETDB1 以不依赖去甲基化酶的方式抑制内源性逆转录因子，例如MMVL30 。这些逆转录因子的去抑制激活细胞溶质 RNA 传感和 DNA 传感通路以及随后的 I 型干扰素反应，导致肿瘤排斥和免疫记忆的诱导。我们的结果表明，KDM5B 通过逆转录元件的表观遗传沉默来抑制抗肿瘤免疫。因此，我们揭示了 KDM5B 在黑色素瘤异染色质调节和免疫逃避中的作用，为开发 KDM5B 靶向和 SETDB1 靶向疗法以增强肿瘤免疫原性和克服免疫疗法耐药性开辟了新途径。