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Preprint WatchModerateSeptember 23rd, 2026

Proton FLASH radiotherapy enhances control of triple-negative breast cancer through STING-IRF3 and CD8+ T-cell immunity

Loap, P.; Paraskevaidis, I.; Cheptea, C.; Kolker, K.; Kim, M.; Setianegara, J.; Singh, K.; Berianu, I. M.; Metz, J.; Greenberg, R. A.; Bilker, W. B.; Berlin, E.; Koumenis, C.; Assenmacher, C.-A.; Diffenderfer, E.; Taunk, N. K.; Verginadis, I. I.

Proton FLASH radiotherapy enhances tumour control through STING-IRF3 signalling and CD8 T-cell immunity, and combined with anti-PD-1 and agonistic anti-CD40 produces durable complete responses in murine triple-negative breast tumours.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The combination arm of this preprint pairs radiotherapy with an agonistic anti-CD40 antibody and anti-PD-1, which is the same architecture that Claidex already records as a clinical failure. In gen1042-cd40-4-1bb-immunoradiotherapy-solid-tumors-phase1-2-efficacy-termination, a CD40 by 4-1BB bispecific given as immunoradiotherapy in metastatic non-CNS solid tumours was terminated for efficacy. That is a direct archetype match, so the flag is graded MODERATE on a single prior failure. Two further Claidex entries at the PD-1 axis sit alongside it, camrelizumab-apatinib-pdcd1-first-line-cervical-cancer-phase2-efficacy-failure and pds0101-pembrolizumab-pdcd1-hpv16-head-neck-versatile-003-phase3-strategic-reprioritization. The preprint's primary claim is about dose rate rather than about CD40, and its comparison of FLASH against standard proton delivery is internally controlled, so the novel element is not the immunotherapy backbone. The caution is narrow and specific. Murine complete responses under radiation plus CD40 agonism plus PD-1 blockade have not previously predicted clinical benefit at this target, and the preprint does not test whether dose rate changes that.

Abstract excerpt

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.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.