{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T09:28:47Z","timestamp":1786699727598,"version":"build-2736575974"},"reference-count":58,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: The abscopal effect refers to the clinical response of non-irradiated tumor lesions following localized radiotherapy (RT). Once regarded as a rare phenomenon, it has gained renewed interest in the era of immunotherapy, as RT may promote systemic anti-tumor immune responses. This narrative review summarizes current biological, radiobiological, and clinical evidence on the abscopal effect and highlights translational gaps limiting its reproducibility. Methods: Preclinical, translational, and clinical evidence was qualitatively analyzed across seven domains: RT, immunology, and clinical oncology. A structured qualitative gap analysis was used to identify disconnections between biological mechanisms, RT parameters, biomarkers, and clinical outcomes. Results: Current evidence supports the biological plausibility of the abscopal effect through immunogenic cell death, antigen and damage-associated molecular patterns (DAMP) release, activation of the cyclic GMP\u2013AMP synthase\u2013stimulator of interferon genes (cGAS-STING) pathway, dendritic-cell priming, and T-cell-mediated responses. However, clinical results remain heterogeneous. Dose, fractionation, irradiated volume, timing, lymphocyte preservation, and interventional RT (modern brachytherapy, IRT) may influence systemic immune activation. Emerging biomarkers, particularly extracellular vesicles (EVs), may help connect radiation-induced biological stress with immune modulation and clinical response. Conclusions: The main barrier to clinical translation is the fragmentation of evidence across RT, immunology, and clinical oncology. Integrated translational frameworks combining dosimetry, immune monitoring, EVs-based biomarkers, imaging, and clinical endpoints may improve the interpretation and reproducibility of abscopal responses in immuno-RT.<\/jats:p>","DOI":"10.3390\/biom16081185","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T08:08:29Z","timestamp":1786694909000},"page":"1185","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Revisiting the Abscopal Effect in the Era of Immuno-Radiotherapy: Mechanisms, Challenges, and Clinical Perspectives"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1666-012X","authenticated-orcid":false,"given":"Enrico","family":"Rosa","sequence":"first","affiliation":[{"name":"Sezione di Fisica, Dipartimento di Neuroscienze, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Roma, Italy"},{"name":"UOC Fisica per le Scienze della Vita, Dipartimento di Diagnostica per Immagini e Radioterapia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Vaccaro","sequence":"additional","affiliation":[{"name":"UOC Fisica per le Scienze della Vita, Dipartimento di Diagnostica per Immagini e Radioterapia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3368-1810","authenticated-orcid":false,"given":"Bruno","family":"Fionda","sequence":"additional","affiliation":[{"name":"UOC Degenze per la Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini e Radioterapia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3507-7051","authenticated-orcid":false,"given":"Valentina","family":"Lancellotta","sequence":"additional","affiliation":[{"name":"UOC Degenze per la Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini e Radioterapia Oncologica, Fondazione Policlinico Universitario A. 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Gemelli IRCCS, 00168 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6618-3122","authenticated-orcid":false,"given":"Lucia","family":"Di Maio","sequence":"additional","affiliation":[{"name":"UOC Degenze per la Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini e Radioterapia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Marazzi","sequence":"additional","affiliation":[{"name":"UOC Degenze per la Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini e Radioterapia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Marampon","sequence":"additional","affiliation":[{"name":"Department of Radiological Sciences, Oncology, and Anatomical Pathology, Sapienza University of Rome, Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3422-6812","authenticated-orcid":false,"given":"Monica","family":"Mangoni","sequence":"additional","affiliation":[{"name":"Radiotherapy Unit, Department of Experimental & Clinical BiomedicalSciences, University of Florence, Largo Brambilla 3, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5455-8737","authenticated-orcid":false,"given":"Maria Antonietta","family":"Gambacorta","sequence":"additional","affiliation":[{"name":"UOC Servizio di Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini e Radioterapia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy"},{"name":"Dipartimento di Scienze Radiologiche ed Ematologiche, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4260-5107","authenticated-orcid":false,"given":"Marco","family":"De Spirito","sequence":"additional","affiliation":[{"name":"Sezione di Fisica, Dipartimento di Neuroscienze, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Roma, Italy"},{"name":"UOC Fisica per le Scienze della Vita, Dipartimento di Diagnostica per Immagini e Radioterapia Oncologica, Fondazione Policlinico Universitario A. 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