Senescence-Driven Inflammation and Immune Dynamics in the Progression of Radiation Cystitis

Pelvic radiation therapy is an essential treatment for several pelvic malignancies, but can lead to radiation cystitis (RC), a severe progressive inflammatory bladder disorder lacking effective diagnosis and therapeutic options. RC evolves through acute, latent, and chronic phases, ultimately resulting in bladder fibrosis, vascular damage, and hematuria. Here, we characterize the molecular and immunological mechanisms underlying RC progression using a preclinical mouse model. Building on prior analysis of the acute and chronic phases, we examined the previously unanalyzed latent phase and integrated transcriptomic, immune cell profiling, inflammatory protein measurements, and bladder function assessments across all stages. Acute radiation injury was marked by strong activation of apoptotic pathways, whereas latent and chronic phases were dominated by inflammatory signaling with distinct cytokine and chemokine signatures. Persistent upregulation of Cdkn1a (P21) suggested sustained senescence, while reductions in IL-27 and shifts in granulocyte–lymphocyte proportions during the latent phase indicated impaired immune surveillance. At chronic stages, increased SASP-associated proteins and matrix-remodeling mediators coincided with bladder functional decline. Together, these findings support a model in which radiation-induced senescence, coupled with immune dysregulation during the latent phase, drive ongoing inflammation, tissue remodeling, and bladder dysfunction in RC.