Bimetallic nanoparticles as cascade sensitizing amplifiers for low-dose and robust cancer radio-immunotherapy

Radiotherapy(RT)is one of the most feasible and routinely used therapeutic modalities for treating malignant tumors.In particular,immune responses triggered by RT,known as radio-immunotherapy,can partially inhibit the growth of distantly spreading tumors and recurrent tumors.How-ever,the safety and efficacy of radio-immunotherapy is impeded by the radio-resistance and poor immu-nogenicity of tumor.Herein,we report oxaliplatin(IV)-iron bimetallic nanoparticles(OXA/Fe NPs)as cascade sensitizing amplifiers for low-dose and robust radio-immunotherapy.The OXA/Fe NPs exhibit tumor-specific accumulation and activation of OXA(I)and Fe^(2+)in response to the reductive and acidic microenvironment within tumor cells.The cascade reactions of the released metallic drugs can sensitize RT by inducing DNA damage,increasing ROS and O_(2) levels,and amplifying the immunogenic cell death(ICD)effect after RT to facilitate potent immune activation.As a result,OXA/Fe NPs-based low-dose RT triggered a robust immune response and inhibited the distant and metastatic tumors effectively by a strong abscopal effect.Moreover,a long-term immunological memory effect to protect mice from tumor rechal-lenging is observed.Overall,the bimetallic NPs-based cascade sensitizing amplifier system offers an effi-cient radio-immunotherapy regimen that addresses the key challenges.

Oxygen-driven cuproptosis synergizes with radiotherapy to potentiate tumor immunotherapy

The immunological implications of cuproptosis,a form of cell death highly sensitive to oxygen presence,remain largely unexplored in the context of tumor immunother-apy.Herein,we initially investigate the positive correlation between cuproptosis and tumor immunotherapy through bioinformatics analysis.Subsequently,an oxygen generator loaded with copper ions(Cu/APH-M)has been constructed,which serves as an effective carrier of copper ions and crucially enhances the oxygenation of the tumor microenvironment.Importantly,Cu/APH-M-mediated dual strengthening of cuproptosis and radiotherapy could not only trigger a powerful antitumor immunity related to immunogenic cell death by RNA-sequencing analysis,but also effec-tively inhibit the growth of both distal and in situ low rectal tumors after combined immunotherapy,creating a robust immune memory effect.Our work reveals the ben-eficial effects of enhanced cuproptosis in radio-immunotherapy and elucidates its underlying mechanisms,which provides a novel approach for the synergistic inte-gration of cuproptosis with immunotherapy and radiotherapy,broadening the scope of cuproptosis-mediated tumor therapy.