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Recurrent mutations in core spliceosomal components, including SF3B1, SRSF2, U2AF1, and ZRSR2, are common in myeloid malignancies, while dysregulated splicing regulators and cis-acting splice-site alterations shape cancer-relevant isoform programs across solid tumors. Together with high transcriptional output, rapid proliferation, and oncogene-driven RNA-processing demand, these alterations can reduce the capacity of cancer cells to tolerate additional splicing perturbation, creating a therapeutic window for pharmacological splicing modulation. Multiple strategies are under investigation, including SF3B complex modulators, splicing kinase inhibitors, RBM39-directed molecular glues, PRMT\/arginine-methylation-directed approaches, and selected splice-switching strategies. Early clinical experience indicates that pharmacodynamic modulation of splicing is achievable in patients, yet objective clinical benefit has been inconsistent. This reflects narrow therapeutic windows, incomplete concordance between peripheral-blood pharmacodynamic markers and tumor-tissue splicing perturbation, and the limited predictive value of mutation status alone. Rational combinations with apoptosis-targeted agents, oncogene-directed therapies, DNA-damaging agents, PARP inhibitors, and immunotherapies may offer a more effective route to clinical translation than maximal single-agent splicing inhibition. Continued progress will require more selective splicing-directed modalities, pharmacodynamic biomarkers that measure splicing perturbation in the relevant tumor or blood compartment, longitudinal mapping of genetic and tumor cell-state plasticity-driven resistance, and biomarker-defined combination trials to support expansion from hematologic malignancies into solid tumors.<\/jats:p>","DOI":"10.1093\/jjco\/hyag140","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T11:26:09Z","timestamp":1786361169000},"source":"Crossref","is-referenced-by-count":1,"title":["Splicing modulation as an emerging therapeutic strategy in cancer: molecular mechanisms, clinical development, and future perspectives"],"prefix":"10.1093","author":[{"given":"Xinbate","family":"Jingele","sequence":"first","affiliation":[{"name":"Division of Cancer RNA Research, National Cancer Center Research Institute , 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045 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and Tumor Biology, The Institute of Medical Science, The University of Tokyo , 4-6-1 Shirokanedai, Minato-ku, Tokyo 108- 8639 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuerui","family":"Tao","sequence":"additional","affiliation":[{"name":"Division of Cancer RNA Research, National Cancer Center Research Institute , 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0664-7281","authenticated-orcid":false,"given":"Akihide","family":"Yoshimi","sequence":"additional","affiliation":[{"name":"Division of Cancer RNA Research, National Cancer Center Research Institute , 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045 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