Proton FLASH radiotherapy enhances control of triple-negative breast cancer through STING-IRF3 and CD8+ T-cell immunity
- 1Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Abstract
FLASH radiotherapy delivers radiation at ultra-high dose rates and has been demonstrated to spare normal tissue compared to standard radiotherapy, but it is not known if dose rate also modifies tumor response. Here we compare a single 13.5 Gy fraction of proton irradiation delivered at FLASH (F-PRT) or Standard (S-PRT) dose rate in immunocompetent C57BL/6 mice bearing EO771 or AT3 triple-negative mammary tumors. At this identical physical dose, F-PRT delays tumor growth more than S-PRT at both heterotopic and orthotopic sites. The effect is largest in EO771, where F-PRT also prolongs tumor-volume endpoint-free survival and reduces the emergence of lung metastases relative to S-PRT. F-PRT induces earlier intratumoral STING expression and IRF3 nuclear translocation, higher type I interferon levels and greater CD8+ T-cell infiltration. CD8+ T-cell depletion or systemic STING inhibition abolishes the F-PRT advantage. Combined with anti-PD-1 and agonistic anti-CD40, both modalities produce durable complete responses that reject contralateral rechallenge, but F-PRT limits tumor progression before response and accelerates regression. FLASH proton radiotherapy not only improves normal-tissue tolerance, but also antitumor immunity, suggesting that ultra-high dose rate could widen the therapeutic window from both sides.
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BibTeX
@misc{loap2026proton,
title = {{Proton FLASH radiotherapy enhances control of triple-negative breast cancer through STING-IRF3 and CD8+ T-cell immunity}},
author = {P. Loap and I. Paraskevaidis and C. Cheptea and K. Kolker and M. Kim and J. Setianegara and K. Singh and I. M. Berianu and J. Metz and R. A. Greenberg and W. B. Bilker and E. Berlin and C. Koumenis and C.-A. Assenmacher and E. Diffenderfer and N. K. Taunk and I. I. Verginadis},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.19.751623},
url = {https://www.biorxiv.org/content/10.64898/2026.09.19.751623v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Proton FLASH radiotherapy enhances control of triple-negative breast cancer through STING-IRF3 and CD8+ T-cell immunity
AU - P. Loap
AU - I. Paraskevaidis
AU - C. Cheptea
AU - K. Kolker
AU - M. Kim
AU - J. Setianegara
AU - K. Singh
AU - I. M. Berianu
AU - J. Metz
AU - R. A. Greenberg
AU - W. B. Bilker
AU - E. Berlin
AU - C. Koumenis
AU - C.-A. Assenmacher
AU - E. Diffenderfer
AU - N. K. Taunk
AU - I. I. Verginadis
PY - 2026
DA - 2026/09/19
PB - bioRxiv
DO - 10.64898/2026.09.19.751623
UR - https://www.biorxiv.org/content/10.64898/2026.09.19.751623v1
AB - FLASH radiotherapy delivers radiation at ultra-high dose rates and has been demonstrated to spare normal tissue compared to standard radiotherapy, but it is not known if dose rate also modifies tumor response. Here we compare a single 13.5 Gy fraction of proton irradiation delivered at FLASH (F-PRT) or Standard (S-PRT) dose rate in immunocompetent C57BL/6 mice bearing EO771 or AT3 triple-negative mammary tumors. At this identical physical dose, F-PRT delays tumor growth more than S-PRT at both heterotopic and orthotopic sites. The effect is largest in EO771, where F-PRT also prolongs tumor-volume endpoint-free survival and reduces the emergence of lung metastases relative to S-PRT. F-PRT induces earlier intratumoral STING expression and IRF3 nuclear translocation, higher type I interferon levels and greater CD8+ T-cell infiltration. CD8+ T-cell depletion or systemic STING inhibition abolishes the F-PRT advantage. Combined with anti-PD-1 and agonistic anti-CD40, both modalities produce durable complete responses that reject contralateral rechallenge, but F-PRT limits tumor progression before response and accelerates regression. FLASH proton radiotherapy not only improves normal-tissue tolerance, but also antitumor immunity, suggesting that ultra-high dose rate could widen the therapeutic window from both sides.
ER -