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Updated: Nov 21, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer
Elizabeth A Bowling1, Jarey H Wang2, Fade Gong1
1Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
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.
Insights
Spliceosome-targeted therapies (STTs) trigger cancer cell death by causing mis-spliced RNA to mimic viral infections, activating innate antiviral immune responses and apoptosis in tumors.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Oncogenic factors disrupt RNA splicing, making tumors sensitive to spliceosome-targeted therapies (STTs).
- The precise mechanisms of STT-induced cancer cell death are not fully understood.
Purpose of the Study:
- To elucidate how STTs selectively eliminate cancer cells.
- To investigate the role of mis-spliced RNA in mediating tumor cell death and immune responses.
Main Methods:
- Utilized MYC-driven triple-negative breast cancer models.
- Analyzed RNA splicing aberrations and their downstream effects in response to STTs.
- Investigated dsRNA-binding protein interactions and antiviral signaling pathways.
- Correlated RNA mis-splicing with immune signatures in human breast cancer samples.
Main Results:
- STTs induce cytoplasmic accumulation of mis-spliced mRNAs, forming double-stranded RNA (dsRNA) structures.
- Endogenous dsRNAs are recognized by dsRNA-binding proteins, initiating antiviral signaling and apoptosis.
- STTs activate intrinsic antiviral signaling, promoting adaptive immune responses and tumor cell death in immune-competent models.
- RNA mis-splicing correlates with immune signatures in human breast cancers, particularly in MYC-amplified tumors.
Conclusions:
- Mis-spliced RNA acts as a molecular trigger for tumor killing via viral mimicry.
- dsRNA-sensing pathways are activated by global RNA splicing aberrations in cancer.
- STTs hold potential for novel anti-tumor immune strategies by activating immune pathways.
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