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Tumour hypoxia is a well‐established factor of resistance in radiation therapy (RT). Myo‐inositol trispyrophosphate (ITPP) is an allosteric effector that reduces the oxygen‐binding affinity of haemoglobin and facilitates the release of oxygen by red blood cells. We investigated herein the oxygenation effect of ITPP in six tumour models and its radiosensitizing effect in two of these models. The evolution of tumour pO2 upon ITPP administration was monitored on six models using 1.2 GHz Electron Paramagnetic Resonance (EPR) oximetry. The effect of ITPP on tumour perfusion was assessed by Hoechst staining and the oxygen consumption rate (OCR) in vitro was measured using 9.5 GHz EPR. The therapeutic effect of ITPP with and without RT was evaluated on rhabdomyosarcoma and 9L‐glioma rat models. ITPP enhanced tumour oxygenation in six models. The administration of 2 g/kg ITPP once daily for 2 days led to a tumour reoxygenation for at least 4 days. ITPP reduced the OCR in six cell lines but had no effect on tumour perfusion when tested on 9L‐gliomas. ITPP plus RT did not improve the outcome in rhabdomyosarcomas. In 9L‐gliomas, some of tumours receiving the combined treatment were cured while other tumours did not benefit from the treatment. ITPP increased oxygenation in six tumour models. A decrease in OCR could contribute to the decrease in tumour hypoxia. The association of RT with ITPP was beneficial for a few 9L‐gliomas but was absent in the rhabdomyosarcomas.

The reprogramming of tumor-associated macrophages (TAMs) by radiotherapy is associated with cancer patient's response and sensitization to immune checkpoint blockade, but the molecular mechanisms involved remain largely unknown. Here, we show that following ionizing radiation (IR), macrophages accumulate single and double strand-DNA breaks and fragmented mitochondria in their cytosol, and stabilize the DNA sensor cyclic GMP-AMP synthase (cGAS). We demonstrate that mitochondrial fragmentation is induced by the activation of the dynamin-related protein 1 (DRP1), and controls the stabilization of cGAS and the proinflammatory activation of irradiated macrophages. Furthermore, pharmacological and genetic inhibitions of cGAS impair the proinflammatory activation of irradiated macrophages, thus revealing that cGAS is a central effector of IR-mediated proinflammatory macrophage activation. Interestingly, we also report that the purinergic receptor P2Y2 acts as an endogenous repressor of the proinflammatory macrophage activation and demonstrate that P2Y2 inactivation enhances the capacity of irradiated macrophages to undergo a proinflammatory activation. Our results thus define a new signaling pathway elicited in macrophages by IR directing mitochondrial dynamics, cytosolic DNA recognition by cGAS and proinflammatory phenotype, which is enhanced following P2Y2 inactivation.Competing Interest StatementJean-Luc Perfettini is founding member of Findimmune SAS, an Immuno-Oncology Biotech company. Jean-Luc Perfettini disclosed research funding not related to this work from NH TherAguix and Wonna Therapeutics.

Background: Tumor-associated macrophages (TAMs) are essential components of the inflammatory microenvironment of tumors and are associated with poor clinical outcomes in the majority of cancers. TAMs mainly exhibit anti-inflammatory functions that promote and support the tissue remodeling, the immune suppression and the tumor growth. Regarding their plasticity, the functional reprogramming of anti-inflammatory TAMs into proinflammatory phenotype recently emerged as a therapeutic opportunity to improve the effectiveness of anticancer treatments such as radiotherapy. Results: Here we show that gadolinium-based nanoparticles AGuIX alone and in combination with ionizing radiation (IR) induce in a dose-dependent manner, the accumulation of DNA double strand breaks, an Ataxia telangiectasia mutated (ATM)-dependent DNA-damage response, an increased expression of the Interferon regulatory factor 5 (IRF5) and the release of proinflammatory cytokines from targeted macrophages, thus directing their proinflammatory reprogramming. This process is associated with the activating phosphorylation of the Adenosine Monophosphate (AMP) activated protein kinase on threonine 172 (AMPKT172*) and the fragmentation of mitochondria. Furthermore, we demonstrate that the inactivation of AMPK reduces the mitochondrial fragmentation and the proinflammatory reprogramming of macrophages detected in response to AGuIX and their combination with IR. These results reveal that the AMPK-dependent regulation of mitochondrial fragmentation plays a central role during the proinflammatory reprogramming of macrophages. Accordingly, a positive correlation between AMPKT172* and proinflammatory activation of TAMs is detected following IR+AGuIX combination in syngeneic mouse model of colorectal cancer. Conclusions: Altogether, our results identify a novel signaling pathway elicited by AGuIX and their combined treatment with IR, that targets macrophage polarization, skews macrophage functions toward the proinflammatory phenotype and may enhance the effectiveness of radiotherapy.Competing Interest StatementJ.-L.P. reports research grants from NH TherAguix SA and Wonna Therapeutics and is founder of Findimmune SAS, an Immuno-Oncology Biotech company. S.D., T.D. and G.L.D. are currently employees of NH TheraAguix SA. A.A. was employed by NH TheraAguix SA to develop research activities related to the current work. D.T. was recipient of a CIFRE contract in partnership with NH TherAguix SA. J.-L.P. and A.A. are co-inventors on patents (WO2016185026 and WO2018050928), relating to macrophage reprogramming. J.-L.P., A.A., F. L. and O.T are co-inventors on patents (WO2019008040A1; WO2021053173A1), relating to AGuIX and relevant to the current work. J.-L.P., D.T., S.D. and G.L.D. are co-inventors on patent (EP23173710.7), relating to immunomodulatory properties of AGuIX and combinatorial strategies. G.L.D., F.L. and O.T. are co-inventors on patent (WO2011135101), relating to AGuIX. G.L.D., S. D. D., F. L. and O. T. possess shares in NH TheraAguix SA. The remaining authors declare no other competing financial interests.