Hypoxia-Inducible Factor 1α (HIF-1α), which promotes cancer cell survival, is the main regulator of oxygen homeostasis. Hypoxia combined with photon and carbon ion irradiation (C-ions) stabilizes HIF-1α. Silencing HIF-1α under hypoxia leads to substantial radiosensitization of Head-and-Neck Squamous Cell Carcinoma (HNSCC) cells after both photons and C-ions. Thus, this study aimed to clarify a potential involvement of HIF-1α in the detection, signaling, and repair of DNA Double-Strand-Breaks (DSBs) in response to both irradiations, in two HNSCC cell lines and their subpopulations of Cancer-Stem Cells (CSCs). After confirming the nucleoshuttling of HIF-1α in response to both exposure under hypoxia, we showed that silencing HIF-1α in non-CSCs and CSCs decreased the initiation of the DSB detection (P-ATM), and increased the residual phosphorylated H2AX (γH2AX) foci. While HIF-1α silencing did not modulate 53BP1 expression, P-DNA-PKcs (NHEJ-c) and RAD51 (HR) signals decreased. Altogether, our experiments demonstrate the involvement of HIF-1α in the detection and signaling of DSBs, but also in the main repair pathways (NHEJ-c and HR), without favoring one of them. Combining HIF-1α silencing with both types of radiation could therefore present a potential therapeutic benefit of targeting CSCs mostly present in tumor hypoxic niches.

An emerging target to overcome cancer resistance to treatments is copper, which is upregulated in a wide variety of tumors and may be associated with cancer progression and metastases. The aim of this study was to develop a multimodal ultrasmall nanoparticle, CuPRiX, based on the clinical AGuIX nanoparticle made of the polysiloxane matrix on which gadolinium chelates are grafted. Such hybrid nanoparticles allow: (i) a localized depletion of copper in tumors to prevent tumor cell dissemination and metastasis formation and (ii) an increased sensitivity of the tumor to radiotherapy (RT) due to the presence of high Z gadolinium (Gd) atoms. CuPRiX nanoparticles are obtained by controlled acidification of AGuIX nanoparticles. They were evaluated in vitro on two cancer cell lines (lung and head and neck) using the scratch-wound assay and clonogenic cell survival assay. They were able to reduce cell migration and invasion and displayed radiosensitizing properties.

The gastrointestinal tract is a unique immunological environment where the host must balance tolerance to commensal microbes with defense against pathogens. A critical mechanism for maintaining this balance is the peripheral conversion of naïve T cells into regulatory T cells (pTregs), a process that depends on the TGF-β cytokine, which is produced in a latent form and must be activated. While the activation of latent TGF-β relies on the membrane-bound αvβ8 integrin, the precise cellular subset(s) responsible for this essential process have yet to be clearly defined. Conventional dendritic cells (cDCs), which migrate from the intestinal lamina propria to the gut-draining mesenteric lymph nodes (MLN), have long been considered the primary antigen-presenting cells (APCs) responsible for αvβ8-mediated TGF-β activation and pTreg induction. However, recent studies have challenged this paradigm by highlighting a new family of rare RORγt-expressing APCs, able to induce pTreg via αv integrins, raising questions about the in vivo role of cDCs in the maintenance of mucosal immune homeostasis. Using a β8 integrin gene reporter mouse model ( Itgb8-IRES-tdTomato ) combined with single-cell profiling, we comprehensively mapped Itgb8 -expressing APCs in the MLN. We show that cDCs, in particular migratory type 1 (cDC1) and type 2 (cDC2), constitute the predominant Itgb8 ^{TdTomato +} cells, both in neonatal and adult mice. Through cDC subset-specific β8 knockout models, we demonstrate that both cDC1 and cDC2 are required for optimal pTreg generation. Loss of β8 integrin in either subset led to a partial reduction in pTreg, while combined deletion resulted in profound pTreg loss and spontaneous colitis. Importantly, these effects were independent of RORγt⁺ APC populations, including ILC3s and Thetis cells. These findings resolve longstanding questions about the identity of key APCs driving pTreg induction in the MLNs. They demonstrate that cDC1 and cDC2 are non-redundant, essential mediators of pTreg induction and intestinal immune tolerance. Although different populations of RORγt⁺ APCs may contribute in specific contexts, such as early development, infection, or in the prevention of allergic disease, cDCs remain one of the primary guardians of intestinal immune homeostasis in response to microbiota.