| Immunotherapy plays an increasingly important role in tumor therapy by activating the body’s own immunity.The development of immune checkpoint blocking,CAR T and other immunotherapies have made important progress in clinic.However,the existence of immunosuppressive cells and related factors in the tumor immune microenvironment（TIME）makes cancer cells escape from the monitoring of the immune system through various ways,resulting in poor immunotherapy effect.Therefore,it is necessary to develop new immunotherapy strategies according to the characteristics of tumor immunosuppressive microenvironment to improve the anti-tumor effect of immune system.Compared with single immune regulation,multi-directional immune pathway can more effectively reshape tumor immune microenvironment and improve the anti-tumor function of immune cells.In addition,although the current immunotherapy has a good effect on tumor metastasis and recurrence,but the suppression effect on the main tumor is poor.It is the current trend of tumor immunotherapy to make up for the deficiency of immunotherapy in main tumor therapy by other therapeutic methods.Based on this,this paper intends to construct an ovalbumin（OVA）-polyphenol nanovaccine with bidirectional immunomodulatory function,which reshapes the tumor immune microenvironment by promoting the polarization of tumor-associated macrophages（TAMs）and inhibiting the expression of indoleamine 2,3-dioxygenase（IDO）to achieve photothermal-immune combination therapy.The research content is divided into the following three parts:Chapter 1:This chapter mainly introduces the research progress of tumor immunotherapy and the limitations of tumor immune microenvironment on immunotherapy.Then,the polarization of TAMs in the tumor immune microenvironment and the research of IDO blocking immunotherapy are further introduced.Based on these,the importance of reshaping the tumor immune microenvironment was explained,and the necessity of photothermal-immunotherapy was elaborated.Based on the above research background,the topic selection ideas and research significance of this paper are proposed.Chapter 2:By simple Schiff Base reaction,polyphenol Tannic acid（TA）was introduced into the model antigen OVA,and FeⅢ-TA-OVA nanovaccine were prepared by using the coordination properties of polyphenol and metal ions.On the basis of this,the IDO inhibitor 1-methyltryptophan（1-MT）was loaded to obtain FeⅢ-TA-OVA@1-MT nanovaccine.The successful construction of FeⅢ-TA-OVA@1-MT nanovaccine was verified by FT-IR,Raman,circular dichroic and other characterization methods.The photothermal performance and reactive oxygen species generation capacity of Fe III-TA-OVA@1-MT nanovaccine were also explored.Chapter 3:In vitro experiments,the cytotoxicity,tumor cell killing effect,macrophage polarization and dendritic cell maturation of FeⅢ-TA-OVA@1-MT nanovaccine were investigated.Based on the good photothermal-immunotherapy potential in vitro,melanoma models were selected for further in vivo experiments.In unilateral tumor mouse model,the effect of FeⅢ-TA-OVA@1-MT nanovaccine photothermal-immunotherapy in inhibiting tumor growth was investigated.At the same time,the polarization of macrophages and the immune effect of 1-MT were explored.On the basis of unilateral tumor mouse experiments,bilateral tumor mice were carried out to investigate the inhibitory effect of FeⅢ-TA-OVA@1-MT nanovaccine photothermal-immunotherapy on distal tumors,and the immune activation in distal tumors was explored.In view of the characteristics of melanoma easy metastasis,mouse lung metastasis model was constructed.The ability of combination therapy to inhibit tumor metastasis was explored.More importantly,it has been demonstrated that combination therapy can establish long-term effective immune memory in the body. |
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