The Implications of Radiotherapy-Induced Cellular Senescence for Cancer Treatment and Tumor Microenvironment Modulation.

Abstract

Radiotherapy is a cornerstone of cancer management, yet ionizing radiation can induce cellular senescence in tumor cells and in normal or stromal compartments. Senescent cells undergo durable cell-cycle arrest but remain metabolically active and develop the senescence-associated secretory phenotype (SASP), a bioactive secretome that remodels the tumor microenvironment (TME). This review summarizes principal pathways that couple radiation injury to senescence, including persistent DNA damage signaling, oxidative stress driven by reactive oxygen species, telomere dysfunction, and epigenetic reprogramming, and discusses their downstream consequences. We highlight the time- and context-dependent nature of senescence: early after treatment, senescence can constrain proliferation and enhance immune surveillance; when senescent cells persist, chronic SASP signaling can promote extracellular matrix remodeling, angiogenesis, immune dysfunction, cellular plasticity, and ultimately recurrence and therapy resistance, while also contributing to late normal-tissue toxicity and fibrosis. Finally, we evaluate emerging therapeutic strategies to modulate this biology, including senolytics that eliminate senescent cells, senomorphics that attenuate harmful SASP outputs, immunotherapeutic approaches that augment senescence surveillance, and optimization of radiotherapy delivery to limit normal-tissue senescence. Defining robust biomarkers, treatment windows, and safety profiles will be essential for translating senescence-targeted combinations into durable tumor control with reduced long-term toxicity.