Alternative splicing in breast cancer drug resistance: Mechanisms, therapeutic targeting, and clinical translation

Alternative splicing (AS) is a pivotal but underexplored driver of therapeutic resistance in breast cancer. This review provides an integrative synthesis of how AS remodels molecular networks to undermine chemotherapy, endocrine therapy, targeted therapy, and immunotherapy. We highlight specific AS events, such as NCOR2 splice variants in chemoresistance and human epidermal growth factor receptor 2 (HER2) isoforms in anti-HER2 therapy failure, that reshape drug response, survival outcomes, and tumor adaptation. Core mechanisms include splicing factor dysregulation (e.g., SRSF1, SF3A2), stress-induced splice reprogramming, and AS-mediated modulation of apoptosis, immune evasion, and DNA repair. Emerging AS-targeted strategies, notably next-generation splice-switching oligonucleotides and small-molecule spliceosome modulators, have show promising preclinical and early clinical progress, with potential for combination regimens. We further underscore the translational potential of AS as a biomarker platform for precision oncology, encompassing predictive isoform signatures, spliceosome mutation profiling, and liquid biopsy applications, although clinical validation remains ongoing. Collectively, this work outlines a mechanistic and translational framework for exploiting AS to overcome resistance and advance personalized, isoform-informed therapeutic strategies. This review highlights AS-mediated resistance mechanisms, actionable targets and patient-validated biomarkers across major breast cancer therapies.