Alternative Isoforms as Molecular Modulators of Cellular Senescence in Cancer

Cellular senescence is a stress-induced, stable proliferative arrest that acts as a potent barrier to tumorigenesis, yet the senescence-associated secretory phenotype that accompanies it can paradoxically fuel inflammation, angiogenesis and the phenotypic plasticity contributing to tumor heterogeneity, therapy resistance and cancer stem cell emergence. A largely unexplored molecular layer in the senescence program is alternative pre-mRNA splicing, which generates protein isoforms with functionally divergent effects on cell-cycle arrest, apoptosis and the secretory program. More than 90% of human multi-exon genes are alternatively spliced, so most of the nearly 1000 genes linked to senescence are expected to produce several isoforms, yet fewer than twenty have been examined at this level, and direct evidence is available for only about half of these. We review how alternative splicing, together with related mechanisms such as alternative promoter usage and alternative reading-frame selection, modulates distinct outputs of the senescence program, including commitment, persistence, escape and SASP composition, across gene groups such as the TP53/TP63/TP73 family, MDM2/MDM4 and the androgen receptor locus. This evidence ranges from direct causal manipulation to correlative or mechanistically adjacent findings, classified explicitly by evidence level. Direct causal evidence remains limited, making isoform-resolved functional validation a major unmet need in the field.