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Abstract Small cell lung cancer (SCLC) is the most aggressive type of lung cancer with a 5-year overall survival of approximately 5%. SCLC has high prevalence of somatic mutations, yet express low to zero neoantigen. Despite promising advances in immunotherapy, highly metastatic SCLC remains a devastating disease and only a small fraction of SCLC patients respond to immunotherapy. These poor survival and lack of therapy options stresses the unmet need to identify novel and effective targeted therapies for metastatic SCLC. Here, we demonstrate that targeting the splicing core component, SF3B1, in SCLC, is a molecular trigger for tumor killing and viral mimicry. SF3B1 inhibition through the small molecule Pladienolide B (PlaB) induces the accumulation of immunogenic double-stranded RNAs (dsRNAs), including right-handed dsRNA conformation (A-RNA), provoking a tumor-intrinsic innate immune response and tumor cell death in SCLC preclinical models. Strikingly, we discovered that PlaB treatment also induces the formation of Z-form nucleic acids (Z-NAs), which are unique, left-handed nucleic acids and necroptosis-activating ligands for the host sensor ZBP1. These endogenous A-RNAs and Z-NAs initiate tumor-intrinsic antiviral interferon (IFN) signaling in SCLC cells leading to tumor-intrinsic immunogenicity and apoptosis. Notably, we also found that Z-NAs derived from spliceosome inhibition trigger the activation of ZBP1, inducing RIPK3-mediated MLKL activation and eventual necroptosis, a highly immunogenic cell-death pathway, in ‘necroptosis competent’ cells, including mouse embryonic fibroblasts (MEFs). This opens unexplored strategies for spliceosome inhibitors to activate anti-tumor immune pathways not only in tumor cells themselves, but also in cells of the Tumor Microenvironment (TME), which too can break tolerance and enhance anti-tumor T cell responses which is crucial to enhance cancer immunotherapy responses. These findings demonstrate a unique and novel spliceosome-targeted mechanism to remodel the immunosuppressive TME of SCLCs. Also, our study suggests that SF3B1 inhibitors and potentially other spliceosome inhibitors might be used not only to selectively kill tumor cells, but also as compounds to generate Z-NAs in tumor cells and cells of the TME and trigger on-demand necroptosis without need for an active virus infection. Citation Format: Xinpei Jiang, Xueying Ma, Siddharth Balachandran, Israel Cañadas. Spliceosome: A gatekeeper for necroptosis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3731.
Jiang et al. (Fri,) studied this question.