Clinical and translational radiation oncology · 2026
Exploring the role of hydrogen peroxide in the immune microenvironment of hypoxic tumors.
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Geirnaert Febe, Kerkhove Lisa, Everaert Tim, Gevaert Thierry, Dufait Inès, Ridder Mark De
Аннотация
BACKGROUND AND PURPOSE: Hypoxia remains a critical driver of radioresistance. While previous radiosensitizers have been limited by systemic toxicities, combining hydrogen peroxide (H2O2) with sodium hyaluronate (KORTUC) enables safe intratumoral administration. This study investigates how this reoxygenation modulates the tumor immune microenvironment.
MATERIALS AND METHODS: Release of damage-associated molecular patterns (DAMPs) was assessed in H2O2-treated hypoxic CT26 and DLD-1. In vivo, CT26-tumor-bearing mice received i.t H2O2 with sodium hyaluronate and irradiation (IR). Immune infiltration was analyzed via flow cytometry and validated in vitro using human CD3+ T cells and murine bone marrow-derived macrophages (BMDMs) under hypoxia. Hypoxic regions and CD206+ macrophages were spatially quantified in histological sections using HALO software.
RESULTS: H2O2 induced dose-dependent DAMPs levels in hypoxic tumor cells. In vivo and in vitro analysis revealed that H2O2 preserved T-cell infiltration, proliferation and IFN-γ H2O2 significantly reduced the anti-inflammatory macrophages (Mφ2) phenotype (CD206, Arg1) and induced a functional shift towards pro-inflammatory (Mφ1) activity (iNOS), further validated by qPCR in hypoxic BMDMs. Spatial analysis confirmed sustained reoxygenation and a pronounced reduction in Mφ2 colocalization within remaining hypoxic niches.
CONCLUSIONS: Clinically approved H2O2-based radiosensitizer enhances radioresponse through improved reoxygenation while also favoring remodeling of the tumor microenvironment. H2O2 promotes immunogenic cell death, preserves T cell function, and selectively reduces immunosuppressive Mφ2. Collectively, these findings provide a strong rationale for combining H2O2 with IR to alleviate hypoxia-driven immunosuppression and improve clinical outcomes in solid tumors.
MATERIALS AND METHODS: Release of damage-associated molecular patterns (DAMPs) was assessed in H2O2-treated hypoxic CT26 and DLD-1. In vivo, CT26-tumor-bearing mice received i.t H2O2 with sodium hyaluronate and irradiation (IR). Immune infiltration was analyzed via flow cytometry and validated in vitro using human CD3+ T cells and murine bone marrow-derived macrophages (BMDMs) under hypoxia. Hypoxic regions and CD206+ macrophages were spatially quantified in histological sections using HALO software.
RESULTS: H2O2 induced dose-dependent DAMPs levels in hypoxic tumor cells. In vivo and in vitro analysis revealed that H2O2 preserved T-cell infiltration, proliferation and IFN-γ H2O2 significantly reduced the anti-inflammatory macrophages (Mφ2) phenotype (CD206, Arg1) and induced a functional shift towards pro-inflammatory (Mφ1) activity (iNOS), further validated by qPCR in hypoxic BMDMs. Spatial analysis confirmed sustained reoxygenation and a pronounced reduction in Mφ2 colocalization within remaining hypoxic niches.
CONCLUSIONS: Clinically approved H2O2-based radiosensitizer enhances radioresponse through improved reoxygenation while also favoring remodeling of the tumor microenvironment. H2O2 promotes immunogenic cell death, preserves T cell function, and selectively reduces immunosuppressive Mφ2. Collectively, these findings provide a strong rationale for combining H2O2 with IR to alleviate hypoxia-driven immunosuppression and improve clinical outcomes in solid tumors.