The contribution of antitumor immunity to metastatic dormancy is poorly understood. Here we show that the long noncoding RNA Malat1 is required for tumor initiation and metastatic reactivation in mouse models of breast cancer and other tumor types. Malat1 localizes to nuclear speckles to couple transcription, splicing and mRNA maturation. In metastatic cells, Malat1 induces WNT ligands, autocrine loops to promote self-renewal and the expression of Serpin protease inhibitors. Through inhibition of caspase-1 and cathepsin G, SERPINB6B prevents gasdermin D-mediated induction of pyroptosis. In this way, SERPINB6B suppresses immunogenic cell death and confers evasion of T cell-mediated tumor lysis of incipient metastatic cells. On-target inhibition of Malat1 using therapeutic antisense nucleotides suppresses metastasis in a SERPINB6B-dependent manner. These results suggest that Malat1-induced expression of SERPINB6B can titrate pyroptosis and immune recognition at metastatic sites. Thus, Malat1 is at the nexus of tumor initiation, reactivation and immune evasion and represents a tractable and clinically relevant drug target.

抗肿瘤免疫对转移休眠的贡献知之甚少。在这里，我们表明，在乳腺癌和其他肿瘤类型的小鼠模型中，长非编码 RNA Malat1 是肿瘤发生和转移再激活所必需的。Malat1 定位于核斑点以耦合转录、剪接和 mRNA 成熟。在转移细胞中，Malat1 诱导 WNT 配体、自分泌环以促进自我更新和丝氨酸蛋白酶抑制剂的表达。通过抑制 caspase-1 和组织蛋白酶 G，SERPINB6B 可以防止gasdermin D 介导的焦亡诱导。通过这种方式，SERPINB6B 抑制免疫原性细胞死亡，并逃避 T 细胞介导的早期转移细胞的肿瘤溶解。使用治疗性反义核苷酸对 Malat1 进行靶向抑制，以 SERPINB6B 依赖性方式抑制转移。这些结果表明 Malat1 诱导的 SERPINB6B 表达可以滴定转移部位的细胞焦亡和免疫识别。因此，Malat1 处于肿瘤发生、再激活和免疫逃避的关系中，代表了一个易于处理且具有临床相关性的药物靶点。