Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA mis-splicing in human breast cancers correlates with innate and adaptive immune signatures, especially in MYC-amplified tumors that are typically immune cold. These findings indicate that dsRNA-sensing pathways respond to global aberrations of RNA splicing in cancer and provoke the hypothesis that STTs may provide unexplored strategies to activate anti-tumor immune pathways.

许多致癌损伤会解除 RNA 剪接的调节，通常导致肿瘤对剪接体靶向疗法 (STT) 过敏。然而，STT 选择性杀死癌症的机制仍然很大程度上未知。在此，我们发现错误剪接的 RNA 本身是通过病毒拟态杀死肿瘤的分子触发因素。在 MYC 驱动的三阴性乳腺癌中，STT 导致错误剪接的 mRNA 在细胞质中广泛积累，其中许多形成双链结构。双链 RNA (dsRNA) 结合蛋白识别这些内源 dsRNA，触发抗病毒信号传导和外源性细胞凋亡。在乳腺癌的免疫活性模型中，STT 会导致肿瘤细胞固有的抗病毒信号、下游适应性免疫信号和肿瘤细胞死亡。此外，人类乳腺癌中的 RNA 错误剪接与先天性和适应性免疫特征相关，特别是在通常免疫冷的 MYC 扩增肿瘤中。这些发现表明，dsRNA 传感途径对癌症中 RNA 剪接的整体畸变作出反应，并引发了这样的假设：STT 可能提供未经探索的策略来激活抗肿瘤免疫途径。