The SF3b complex is positioned as a disease-modifying hub at the intersection of RNA splicing and cancer biology, and highlights the opportunities and challenges associated with therapeutically targeting spliceosome components in oncology.
Abstract
Aberrant alternative splicing is increasingly recognized as a fundamental driver of cancer initiation and progression. The splicing factor 3b (SF3b) complex, an essential component of the U2 small nuclear ribonucleoprotein (snRNP), plays a pivotal role in branch point sequence (BPS) recognition and in coordinating spliceosome assembly and activation. Recent advances in cryo-electron microscopy (cryo-EM) have revealed the structural plasticity of the SF3b complex, highlighting its dynamic transition between open and closed conformations that stabilize pre-mRNA substrates during the splicing cycle. Genetic and functional perturbations of SF3b, particularly recurrent mutations in its core subunit SF3B1, are frequently observed in human malignancies, most prominently in myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL). These alterations reshape splice site selection, generate aberrant transcript isoforms, and reprogram cancer-relevant signaling pathways. In this review, we integrate current knowledge of the molecular architecture and regulatory dynamics of the SF3b complex with its emerging roles in cancer-associated splicing programs. We discuss the consequences of SF3b mutations and non-mutational dysregulation on transcriptome remodeling, genome stability, and tumor cell fitness, as well as the contribution of post-translational modifications of SF3b components to splicing control. Furthermore, we critically evaluate recent progress in targeting the SF3b complex, focusing on the structural basis of SF3b inhibitors, insights gained from preclinical studies, and lessons learned from early-phase clinical trials. Collectively, this review positions the SF3b complex as a disease-modifying hub at the intersection of RNA splicing and cancer biology, and highlights the opportunities and challenges associated with therapeutically targeting spliceosome components in oncology.
Aberrant pre-mRNA splicing is a pervasive feature of cancer and an emerging therapeutic vulnerability. 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.
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