增强抗肿瘤免疫力的疗法已改变了许多癌症的自然史。因此，利用非重叠机制增加癌细胞的免疫原性仍然是一项优先任务。本研究使用一种新型的RNA甲基转移酶METTL3的酶抑制剂，证明全球性降低N6-甲基腺苷（m6A）可导致双链RNA的形成和深入的细胞内干扰素应答。通过无偏CRISPR筛选，我们确定dsRNA感应和干扰素信号转导是促进T细胞杀伤癌细胞在METTL3抑制之后的主要介质。我们在一系列免疫受限的小鼠模型中显示，尽管METTL3抑制与抗PD1疗法同等有效，但两者联合治疗具有更强的临床前活性。使用SPLINTR条形码技术，我们证明抗PD1和METTL3抑制以不同的方式靶向恶性克隆，并且联合治疗可以克服对单一疗法不敏感的克隆体。这些数据为在临床中使用METTL3抑制剂促进抗肿瘤免疫提供了分子和临床前的理论基础。

Therapies that enhance anti-tumour immunity have altered the natural history of many cancers. Consequently, leveraging non-overlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyltransferase, METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signalling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that whilst METTL3 inhibition is equally efficacious to anti-PD1 therapy, the combination has far greater pre-clinical activity. Using SPLINTR barcoding, we demonstrate that anti-PD1 and METTL3 inhibition target distinct malignant clones and the combination of these therapies overcome clones insensitive to the single agents. These data provide the molecular and pre-clinical rationale for employing METTL3 inhibitors to promote anti-tumour immunity in the clinic.