S3031
Invited Speaker
ESTRO 2026
evaluation for risk stratification and early detection of radiation induced fibrosis. Therapeutically, senolytic agents (e.g., dasatinib/quercetin, BCL-2 family inhibitors) and senomorphic approaches (e.g., mTOR) show promise in preclinical models for attenuating fibrosis without compromising tumor control. Integration with modern radiotherapy techniques and normal tissue dose constraints may enable personalized mitigation strategies. Targeting cellular senescence represents a unifying framework to understand and potentially prevent radiation induced fibrosis. This session will provide attendees with a mechanistic foundation, review emerging biomarkers, and outline ongoing clinical translation efforts aimed at improving long-term outcomes after radiotherapy. 5415 Radiation-induced endothelial cell senescence in lung fibrosis Charles Fouillade ATOMIC Team, Institut Curie, Orsay, France Radiation-induced lung injury remains a significant dose-limiting toxicity in thoracic radiotherapy, yet the cellular and molecular mechanisms driving its side- effects, particularly pulmonary fibrosis, are incompletely understood. Cellular senescence, a state of stable cell cycle arrest accompanied by a pro- inflammatory secretory phenotype (SASP), has emerged as a key biological response to ionizing radiation in the lung. However, the functional diversity of senescent cell populations and their specific contributions to tissue remodeling remain largely unexplored. In this presentation, I will first provide a comprehensive overview of the current landscape of radiation-induced senescence in the lung, highlighting its dual role as both a protective tumor-suppressive mechanism and a driver of chronic tissue dysfunction. Drawing on single-cell RNA sequencing datasets from irradiated lung tissue, I will then address the heterogeneity of senescence transcriptional signatures across distinct cell populations. These data reveal that no single universal senescence program exists, rather, cell-type-specific transcriptional states define functionally distinct senescent subpopulations with divergent paracrine activities. A particular focus will be placed on lung endothelial cells, which display a unique molecular senescence profile following irradiation. I will describe how radiation selectively reprograms the endothelial transcriptome, altering key regulators of vascular homeostasis, inflammation, and extracellular matrix remodeling. These molecular specificities distinguish
promoting their proliferation and therapy resistance. In addition, we find that SASP can spread from senescent to non-senescent GBM cells via activation of the NF-kB pathway which further amplifies the SASP milieu in irradiated tumors. Recent findings from our lab also indicate that SASP factors secreted by senescent GBM cells promote tumor homing of microglia which can promote recurrence. We find that the cellular inhibitor of apoptosis protein 2 (cIAP2) is a critical survival factor for senescent glioma cells. Importantly, SMAC mimetics targeting cIAP2 act as novel senolytics that selectively trigger apoptosis of senescent GBM cells. Using both PDX and immunocompetent mouse models of GBM, we show that the SMAC mimetic birinapant, administered as an adjuvant after radiotherapy, can eliminate senescent GBM cells and prevent the emergence of recurrent tumors. In sum, our findings illustrate how senescence of both stromal and tumor cells promote GBM recurrence via different pathways and underscore the potential utility of adjuvant senolytic therapy for blunting GBM recurrence after radiotherapy. 5414 Radiation senescence tissue fibrosis Deborah E Citrin Radiation Oncology Branch, NCI CCR, Bethesda, MD, USA Radiation-induced fibrosis (RIF) is a late toxicity that limits curative radiotherapy across disease sites. Increasing evidence implicates therapy-induced cellular senescence as a central mechanism linking initial DNA damage to chronic tissue remodeling and dysfunction. Ionizing radiation induces persistent DNA damage responses that drive senescence in fibroblasts, endothelial cells, and epithelial progenitors via the p53/p21 and p16 pathways. Senescent stem cells can impair tissue homeostasis after injury through reduced proliferative capacity and parenchymal depletion. Senescent cells develop a senescence-associated secretory phenotype (SASP), characterized by pro-inflammatory cytokines (e.g., IL-6, TGF- β ), chemokines, and matrix-remodeling enzymes that perpetuate fibroblast activation, myofibroblast differentiation, and extracellular matrix deposition. Crosstalk between senescent stromal cells and immune populations sustains chronic inflammation and impairs tissue regeneration, establishing a feed- forward loop that promotes fibrosis. Metabolic reprogramming, including mitochondrial dysfunction, increased reactive oxygen species, and altered NAD ⁺ /redox balance, further stabilizes the senescent phenotype and amplifies SASP signaling. Biomarkers such as p16 and p21 expression, SA- β -gal activity, and circulating SASP factors are under
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