Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer

Cell. 2021 Jan 21;184(2):384-403.e21. doi: 10.1016/j.cell.2020.12.031. Epub 2021 Jan 14.


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.

Keywords: MYC; RNA splicing in cancer; anti-cancer immunity; antiviral immunity; double-stranded RNA; oncogenic stress; spliceosome-targeted therapies; triple-negative breast cancer; viral mimicry.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptive Immunity / drug effects
  • Animals
  • Antiviral Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • Female
  • Gene Amplification / drug effects
  • Humans
  • Immunity / drug effects*
  • Introns / genetics
  • Mice
  • Molecular Targeted Therapy
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Splicing / drug effects
  • RNA Splicing / genetics
  • RNA, Double-Stranded / metabolism
  • Signal Transduction / drug effects
  • Spliceosomes / drug effects
  • Spliceosomes / metabolism*
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / immunology*
  • Triple Negative Breast Neoplasms / pathology*


  • Antiviral Agents
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Double-Stranded