Combination therapy with hydrogen peroxide and irradiation promotes an abscopal effect in mouse models

Hydrogen peroxide (H₂O₂) induces oxidative stress and cytotoxicity, and can be used for treating cancers in combination with radiotherapy. A product comprising H₂O₂ and sodium hyaluronate has been developed as a radiosensitizer. However, the effects of H₂O₂ on antitumor immunity remain unclear. To investigate the effects of H₂O₂, especially the abscopal effect when combined with radiotherapy (RT), we implanted murine tumor cells simultaneously in two locations in mouse models: the hind limb and back. H₂O₂ mixed with sodium hyaluronate was injected intratumorally, followed by irradiation only at the hind limb lesion. No treatment was administered to the back lesion. The H₂O₂/RT combination significantly reduced tumor growth at the noninjected/nonirradiated site in the back lesion, whereas H₂O₂ or RT individually did not reduce tumor growth. Flow cytometric analyses of the tumor-draining lymph nodes in the injected/irradiated areas showed that the number of dendritic cells increased significantly with maturation in the H₂O₂/RT combination group. In addition, analyses of tumor-infiltrating lymphocytes showed that the number of CD8⁺ (cluster of differentiation 8) T cells and the frequency of IFN-γ⁺ (interferon gamma) CD8⁺ T cells were higher in the noninjected/nonirradiated tumors in the H₂O₂/RT group compared to those in the other groups. PD-1 (programmed death receptor 1) blockade further increased the antitumor effect against noninjected/nonirradiated tumors in the H₂O₂/RT group. Intratumoral injection of H₂O₂ combined with RT therefore induces an abscopal effect by activating antitumor immunity, which can be further enhanced by PD-1 blockade. These findings promote the development of H₂O₂/RT therapy combined with cancer immunotherapies, even for advanced cancers.