| Recently,many treatment modalities that can cause immunogenic cell death（ICD）have been applied to assist the immune system to fight cancer.ICD is a novel cell death pattern,which induces cells to express or release death associated molecular patterns（DAMPs）,such as calcium reticulin（CRT）protein,high mobility group protein B1（HMGB1）,etc.When ICD occurs,the non-immunogenic cells will transform into immunogenic cells to trigger anti-tumor immunity in the body.Chemotherapy is one of the most common treatment methods in clinical trials,which is suitable for the majority of cancers.More impressively,some chemotherapy drugs（bortezomib（BTZ）,Doxorubicin（Dox）,oxaliplatin（OxP）,etc.）can result in the cell apoptosis when the concentration is high,while the ICD be induced when the concentration is low.There are some defects when chemotherapy drugs are used as ICD inducers for tumor treatment,such as low rate of immune response,low efficiency of drug accumulation,nonspecific tissue distribution and serious damage to normal tissues,which greatly hinder the development and application of chemotherapy drugs.So it is necessary to develop chemotherapy/immunotherapy strategies with high tumor targeting/responsiveness to improve strong immune response rates and reduce side effects.Therefore,we carried out the following two works in this thesis.It is important to develop combined chemotherapy/immunotherapy strategies with high tumor targeting and/or responsiveness and high immune response rates1.A CaCO3-based chemotherapy/CDT synergetic strategy was designed to enhance chemotherapy/immunotherapy for treating primary and distal tumors.CaCO3 is a safe and acid-responsive inorganic material,which specifically released copper ions(Cu2+)and chemotherapeutic agent（OxP）in the acid tumor tissues.The free OxP and Cu2+played the role of chemotherapy and CDT for preventing the growth of primary tumors.Significantly,the OxP and produced ROS could also induce the ICD of cancer cells to expose CRT and HMGB1for triggering the immune response against distal tumors.With the assistance of the immunoblocking inhibitor（IDOi）,CaCO3/Cu/Pt could effectively inhibit the growth of orthotopic and distal tumors.2.A nano ICD inducer based on Doxorubicin prodrug liposome（HA/Lipid@Pro-Dox） activated byγ-Glutamyl Transferase（γ-GGT）was designed for highly targeted and highly specific chemotherapy/immunotherapy against tumors.HA/Lipid@Pro-Dox can accumulate in tumor tissue through the targeting ability of hyaluronic acid（HA）.Moreover,the activity of Dox was specifically triggered by the overexpressedγ-GGT in tumor tissue,thus achieving the tumor targeted and specific responsive drug delivery.The strategy effectively increases the immunogenic cell death of tumor cells and reduces the toxic effects of chemotherapy drugs on normal cells.The use of a combination of immune checkpoint inhibitor（PD-L1）is expected to induce strong anti-tumor effects and effectively inhibit the growth of distant tumors in vivo. |
