The Molecular Landscape of the Senescence–EMT Interplay: Deciphering Tumour Plasticity Through Molecular Signatures and Multi-Omic Profiling

Therapy-induced senescence (TIS) is a common response to anticancer treatments, characterised by stable cell cycle arrest and the acquisition of a complex senescence-associated secretory phenotype (SASP). Initially regarded as a beneficial mechanism that limits tumour growth, growing evidence indicates that TIS is a highly dynamic and heterogeneous process with context-dependent effects that can either suppress or promote tumour progression. The SASP is a central mediator of tumour plasticity, linking TIS to epithelial-to-mesenchymal transition (EMT), cancer stemness, microenvironmental remodelling, therapeutic resistance, and metastatic dissemination. These findings highlight the therapeutic potential of senotherapeutic approaches, including senolytic and senomorphic agents, as key components of one–two-punch therapeutic strategies to selectively eliminate or modulate persistent senescent cells and improve treatment outcomes. Recent advances in multi-omics technologies, artificial intelligence, and liquid biopsy are further transforming the study of senescence by enabling comprehensive molecular characterisation, biomarker discovery, patient stratification, and real-time monitoring of tumour evolution. Collectively, current evidence supports a paradigm shift in which senescence should be considered a dynamic regulator of tumour plasticity and a promising target for precision oncology strategies.