Metal-organic Framework-based Radiosensitization Platform For Tumor Microenvironment Reprogramming And Synergistic Multimodal Therapies For Antitumor Immunotherapy

Cancer is one of the major diseases that threaten human health,among which breast cancer is one of the most common malignancies in women.Currently,the main treatments for breast cancer include surgical treatment,chemotherapy,and radiation therapy.Radiation therapy is an important part of comprehensive treatment for breast cancer,which can effectively reduce the risk of postoperative cancer recurrence and prolong patient survival.In addition,radiation therapy is also an important palliative treatment for patients with advanced and metastatic breast cancer.However,high-dose radiotherapy for breast cancer may increase the risk of heart disease.Furthermore,the efficacy of radiotherapy is restricted by inherent limiting factors,such as insufficient energy deposition and radioresistance induced by the hypoxic tumor microenvironment.More importantly,due to the limiting role of the immunosuppressive tumor microenvironment,single radiotherapy usually only works on local tumors and is difficult to trigger the immune response of the body to kill distant tumors.In this thesis,we constructed a radiation sensitizing nanoplatform,PCN-224@IrNCs/D-Arg(PCN=porous coordination network,IrNCs=iridium nanocrystals,D-Arg=D-arginine),and used it in combination with photodynamic therapy and nitric oxide(NO)therapy to treat breast cancer and enhance its anti-tumor immune response.This nanoplatform displayed excellent anti-tumor efficacy by integrating numerous strategies,including reprogramming the tumor microenvironment,combining photodynamic treatment and NO therapy,and using high-Z element radiation sensitization.In addition,the synergistic effect of multiple therapeutic modalities and the nanoplatform’s own ability to modulate the immunosuppressive tumor microenvironment resulted in repolarization of pro-tumor M2 macrophages into anti-tumor M1 macrophages.Moreover,by inducing and amplifying immunogenic death to promote antigen presentation and stimulate dendritic cell maturation,the nanoplatform eventually recruits immunocidal T cells to infiltrate the tumor,thereby significantly activating the body’s immune response to kill distant tumors.This thesis reports a new therapy that utilizes reprogramming of the tumor microenvironment to achieve synergistic effects and effective cancer treatment,while enhancing anti-tumor immune response,which is expected to be a simple,safe and effective new way of cancer treatment in the future.