Nanomedicines To Improve The Efficacy Of Immunogenic Cell Death For Cancer Therapy

The tumor suppressive immune microenvironment is an important cause for the compromised therapeutic efficacy of cancer immunotherapy.Immunogenic cell death（ICD）is an effective strategy to improve the tumor immune microenvironment and activate the anti-tumor immune response.However,there are limited drugs or means to produce ICD effects,and the reported ICD inducers are mostly small-molecule compounds.Screening and designing novel structures of ICD inducers is an important strategy to solve the above-mentioned challenges.Nanomaterials are widely used for improving drug delivery efficiency and antitumor efficacy,but generally nanomaterials are only used as inert carriers.In this dissertation,a nanomaterial D47 with ICD activity was innovatively discovered,and thoroughly studied its potential to inhibit tumor progression,both alone and in combination with other immunotherapies.Specific studies include the following.（1）Discovery of ICD inducer D47 and its use in anti-tumor immunotherapy.In vitro experiments screening reveals nanomaterial D47 with ICD effect,and subsequently verified its ability to induce ICD in a variety of tumor cells such as CT26 and 4T1,further verifying that D47 enhances the phagocytosis and activation of dendritic cells.D47 also exhibited anti-tumor activity and improved the tumor immune microenvironment in various mouse tumor models,such as colorectal cancer and breast cancer.Significant synergistic potentiation could be observed when combined with immune checkpoint-blocking antibodies.（2）D47 delivering CD47 siRNA to enhanced phagocytosis of macrophages.The nanomaterial D47 can both induce ICD and act as a carrier,its assembled with CD47 siRNA to form nanocomplex(MNC_CD47i-CALRt),which simultaneously upregulated the"eat me"signal and blocked the"don’t eat me"signal.The nanocomplex was developed to enhance the phagocytosis of macrophages.The preparation conditions of the nanocomplex were firstly investigated and the nanocomplex MNC_CD47i-CALRt was successfully obtained,and then verified the pro-phagocytic effect of MNC_CD47i-CALRt.Meanwhile,MNC_CD47i-CALRtexhibited significant tumor growth inhibitory effects in mouse tumor models.Further results in human-derived tumor cells and organoids showed that MNC_CD47i-CALRtsignificantly enhanced the phagocytosis of macrophages.Finally,the study also investigated the ICD inducer in combination with functional inhibition of indoleamine 2,3-dioxygenase（IDO1）to enhance antitumor immunotherapy.The high expression of IDO1 in both patient and mouse colorectal tumor tissues were found,causing immune escape.Based on this,we constructed a cationic lipid-assisted nanoparticle CLAN_siIDO1that can deliver IDO1 siRNA,and initially validated its gene silencing and target site delivery function.In addition,the combination of CLAN_siIDO1 and ICD inducer can effectively inhibit tumor growth and improve the immune microenvironment in a mouse tumor model.