Tumor Microenvironment Regulation For Enhanced Radioimmunotherapy And PA Imaging Of Immune Microenvironment

Tumors,especially solid tumors,often develop a tumor microenvironment(TME)characterized by hypoxia,microacidity,high reactive oxygen/nitrogen species(ROS/RNS),and immunosuppression in order to meet their rapid growth needs.Tumor Microenvironment(TME).Such a tumor microenvironment facilitates the growth and metastasis of cancer cells,but inhibits the activation of intra-tumor immune cells and reduces the infiltration of immune cells,which hinders the recognition and killing of cancer cells by immune cells and seriously affects the responsiveness and therapeutic effects of chemotherapy,radiotherapy and immunotherapy,and is one of the key reasons for tumor treatment tolerance.Therefore,there is an urgent need to develop material systems that can modulate TME to achieve tumor treatment efficacy;in addition,in order to investigate the immune response mechanism during tumor treatment,it is necessary to develop probes that can monitor tumor immune microenvironment in real time,in order to provide a powerful research tool for tumor immunotherapy.In summary,based on the importance of tumor microenvironment in tumor therapy,this master thesis firstly designed a nano-ligand polymer that could improve the lack of oxygen and enhance the immune response to boost radioimmunotherapy;secondly,we also constructed a fluorescent probe that could monitor the activity of cytotoxic T lymphocytes(CTLs)in real time to help immunotherapy efficacy prediction.The main studies are summarized as follows:Chapter 1:Introduces the basic situation of tumor microenvironment,summarizes the efficacy enhancement strategies of tumor immunotherapy based on tumor microenvironment regulation,summarizes the existing imaging modalities of tumor immune microenvironment,and highlights the rationale for the selection of this research paper and the research content.Chapter 2:Radiotherapy(RT)is a widely used clinical cancer treatment strategy,but there is still a need to further improve its specificity and efficacy for lesion sites,and to reduce radiation damage to normal tissues during treatment and effectively inhibit tumor metastasis and recurrence.Therefore,in this chapter,multifunctional nano-ligand polymers(HNP NPs)composed of Hf4+ with 2-nitroimidazole(2-nIm)ligands are designed as a system for sensitizing radioimmunotherapy.X-rays can induce controlled release of nitric oxide(NO)molecules from HNP NPs during radiotherapy,and the released NO can both improve the tumor hypoxic microenvironment and sensitize radiotherapy,and stimulate the proliferation of intratumoral infiltrating T cells.Hf4+ as a high-Z element has good X-ray energy deposition ability,which enhances the killing of tumor cells and reduces the damage to normal tissue cells by radiotherapy;meanwhile,we found that Hf4+ can activate the cellular cGAS-STING pathway and enhance the recognition of tumor cells by immune cells,thus generating a strong immune response,thus improving the limitation of radiotherapy in local treatment and effectively activating systemic immunity to inhibit tumor metastasis and recurrence.Chapter 3:Activation of cytotoxic T lymphocytes(CTLs)is crucial for tumor immunotherapy,and accurate measurement of CTLs activity in vivo is a powerful tool for efficacy assessment of tumor immunotherapy.We designed a fluorescent/photoacoustic probe QSY21-GIEPD-Cy5.5(QIC)based on granzyme B(GzmB,a biomarker closely related to the activation of CTLs)imaging,which can monitor the activation of CTLs in vivo in a real-time and sensitive manner to achieve real-time,non-invasive monitoring of tumor immunotherapy efficacy.Therefore,in this master thesis,we systematically investigated tumor therapy potentiation strategies based on tumor microenvironment modulation and designed a radioimmunotherapy potentiation system for the depleted oxygen microenvironment;we also designed a fluorescent/photoacoustic probe for tumor immunotherapy efficacy prediction by detecting the activation of CTLs.It has been shown that NO alleviates the oxygen deficiency in solid tumor TME by promoting tumor angiogenesis,and increases oxygen supply to significantly improve the efficacy of radiotherapy;meanwhile,hafnium ions have immunostimulatory effects and can activate the innate immunity of the organism to achieve radioimmunotherapy potentiation.In addition,responsive photoacoustic imaging of GzmB,a biomarker of CTLs activation,can effectively monitor the process of tumor immunotherapy and help in the selection of treatment regimens.