胰腺导管腺癌 (PDAC) 是最致命的癌症之一，其致命性和治疗选择有限，包括使用检查点阻断 (ICB) 免疫疗法。表观遗传失调是肿瘤发生的一个决定性特征，与免疫监视有关，但在 PDAC 中仍然难以捉摸。为了确定调节免疫监视的因素，我们在移植到免疫功能正常的小鼠 PDAC 肿瘤模型中采用了体内表观遗传 CRISPR-Cas9 筛选。在这里，我们确定 MED12 是热门产品，成为 PDAC 中免疫肿瘤微环境 (TME) 的有效负调节剂。 Med12 的缺失显着促进了肿瘤中免疫细胞的浸润和细胞毒性，包括 CD8 T 细胞、自然杀伤 (NK) 和 NK1.1 T 细胞，从而提高了 PDAC 小鼠模型中 ICB 治疗的敏感性。从机制上讲，MED12 稳定异染色质蛋白 HP1A，以抑制 H3K9me3 标记的内源性逆转录因子。 MED12 缺失引起的逆转录转座子的去抑制触发了胞质核酸感应和随后 I 型干扰素途径的激活，最终导致 TME 严重发炎。此外，我们发现 MED12 表达与免疫应答途径、逆转录转座子水平以及接受 ICB 治疗的 PDAC 患者的预后之间呈负相关。 总之，我们的研究结果强调了 MED12 通过表观遗传沉默在重塑免疫 TME 中的关键作用。逆转录转座子，为增强肿瘤免疫原性和克服 PDAC 免疫治疗耐药性提供潜在的治疗靶点。© 作者（或其雇主）2024。禁止商业重复使用。请参阅权利和权限。英国医学杂志出版。

Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by its lethality and limited treatment options, including the utilisation of checkpoint blockade (ICB) immunotherapy. Epigenetic dysregulation is a defining feature of tumourigenesis that is implicated in immune surveillance, but remains elusive in PDAC.To identify the factors that modulate immune surveillance, we employed in vivo epigenetic-focused CRISPR-Cas9 screen in mouse PDAC tumour models engrafted in either immunocompetent or immunodeficient mice.Here, we identified MED12 as a top hit, emerging as a potent negative modulator of immune tumour microenviroment (TME) in PDAC. Loss of Med12 significantly promoted infiltration and cytotoxicity of immune cells including CD8+ T cells, natural killer (NK) and NK1.1+ T cells in tumours, thereby heightening the sensitivity of ICB treatment in a mouse model of PDAC. Mechanistically, MED12 stabilised heterochromatin protein HP1A to repress H3K9me3-marked endogenous retroelements. The derepression of retrotransposons induced by MED12 loss triggered cytosolic nucleic acid sensing and subsequent activation of type I interferon pathways, ultimately leading to robust inflamed TME . Moreover, we uncovered a negative correlation between MED12 expression and immune resposne pathways, retrotransposon levels as well as the prognosis of patients with PDAC undergoing ICB therapy.In summary, our findings underscore the pivotal role of MED12 in remodelling immnue TME through the epigenetic silencing of retrotransposons, offering a potential therapeutic target for enhancing tumour immunogenicity and overcoming immunotherapy resistance in PDAC.© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.