ESTRO 2025 - Abstract Book

S30

Invited Speaker

ESTRO 2025

triggered by radiotherapy-induced DNA damage, and the induction is now considered to be a key factor in achieving a systemic therapeutic effect when radiotherapy and immunotherapy are combined.

It is now evident that radiotherapy can modulate the local or systemic immune environment beyond the local elimination of cancer cells, and thus the accumulating evidence renders radiotherapy as a partner for cancer immunotherapy. With high expectations for the combination of immunotherapy and radiotherapy, a thorough understanding of these immune responses will help to maximize its benefits. It has the potential to improve outcomes for patients who currently do not benefit sufficiently from combined treatment.

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Speaker Abstracts Epigenetic mechanisms in DNA double-strand break repair: A possible target for improving response to radiotherapy Matteo Cassandri 1 , Deborah Pajalunga 2 , Simona Camero 1 , Valeria Manzi 3 , Luisa Milazzo 4 , Francesca Vulcano 4 , Valentina Lulli 4 , Silvia Pomella 5 , Francesca Megiorni 1 , Franco Locatelli 6 , Rossella Rota 6 , Francesco Marampon 3 1 Experimental Medicine, University of Rome, Sapienza, Rome, Italy. 2 Istituto Superiore di Sanità, Department of Oncology and Molecular Medicine, Rome, Italy. 3 Radiology, Radiotherapy, Oncology, University of Rome, Sapienza, Rome, Italy. 4 Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy. 5 Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy. 6 Department of Hematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy Epigenetic changes—genetic modifications that impact gene activity without altering the DNA sequence—have emerged as key players in the intricate complexities of cancer biology, driving remarkable heterogeneity and contributing to the persistent challenge of therapy resistance. These modifications dynamically regulate gene expression in response to external stimuli, fueling adaptive changes that enable cancer cells to survive and thrive even under therapeutic stress. Notably, epigenetic mechanisms play a critical role in determining which cells retain the self-renewal capacity acquired during treatment. These cells, referred to as cancer stem cells (CSCs), are responsible for driving long-term cancer growth, therapy failure, and disease progression. Interestingly, CSCs have demonstrated a heightened tolerance to DNA damage, with epigenetic regulation significantly influencing DNA damage/repair processes. Consequently, epigenetic modifications impact transcription, DNA damage response signaling, and genomic stability—hallmarks of cancer radioresistance. Crucially, unlike genetic mutations, epigenetic modifications are reversible, presenting an opportunity for anti cancer radiosensitizing therapies that target epigenetic alterations. However, the full scope of epigenetic changes in cancer, their influence on tumor heterogeneity, and their interactions with DNA double-strand breaks and radioresistance remain largely unexplored. The major epigenetic modifications involved in gene regulation include histone tail modifications, DNA methylation, chromatin remodeling, and post-translational ATP-dependent modifications, such as small non-coding RNA expression and gene imprinting. In this presentation, we will discuss the mechanisms and implications of epigenetics in DNA double-strand break repair, as well as their potential role as therapeutic targets to enhance radiotherapy response. We will focus on how DNA methylation and chromatin modifications affect cellular plasticity at various disease stages, with particular attention to chromatin acetylation/deacetylation mechanisms, "epigenetic writers," and both preclinical and clinical data available in the literature. Abstract: