The evolving role of alternative splicing in cancer stem cell plasticity: From mechanisms to clinical opportunities.

Despites alternative splicing (AS) has long been recognized as a fundamental post-transcriptional process, dysregulation of AS has emerged as a hallmark of cancer, contributing to tumour heterogeneity, progression, and therapy resistance which are the major challenges in current cancer treatment. AS serves as a dynamic adaptive mechanism by expressing pro-survival isoforms in cancer, driving cancer plasticity at both molecular and phenotypical levels. This explains, in large part, the acquisition and maintenance of cancer stem cell (CSC) characteristics including stemness, self-renewal, therapeutic resistance, epithelial-mesenchymal transition (EMT), invasion, metastasis, senescence, metabolic reprogramming, and immune evasion. This review discusses on how cancer cells exploit AS by modulating key splicing regulators, particularly members of the SRSF and hnRNP families, in response to tumour growth associated stress and tumour microenvironment cues throughout cancer progression and therapeutic pressures. Additionally, the intricate relationship between AS and CSCs plasticity is explored. Five splicing regulators including SRSF1, SRSF3, SRSF10, hnRNPA1 and hnRNPI were identified as central players implicated in at least four distinct CSC-associated traits. Among these, stemness, therapeutic resistance, EMT, and senescence are the most prominently regulated via AS regulatory axis. Finally, the clinical opportunities of AS as a biomarker and prognostic indicator, alongside its therapeutic promises is discussed with particular emphasis on targeting splicing regulators to disrupt cancer-specific splicing events, offering promising avenues for the development of novel and effective cancer treatments.