Paraptosis Inducer to Effectively Trigger Immunogenic Cell Death for Metastatic Tumor Immunotherapy with IDO Inhibition

摘要

Paraptosis is characterized by the extensive vacuolizationof endoplasmicreticulum (ER) and mitochondria, which will cause the release of damage-associatedmolecular patterns to promote immunogenic cell death (ICD). However,the tumor can develop an immunosuppressive microenvironment to affectthe ICD activation for the purpose of immune escape. Herein, a paraptosisinducer (CMN) is constructed to amplify the ICD effect for efficientimmunotherapy by inhibiting the activity of indoleamine 2,3-dioxygenase(IDO). Initially, CMN is prepared by the assembly of copper ions (Cu2+), morusin (MR), and IDO inhibitor (NLG919) through noncovalentinteractions. Without the need for extra drug carriers, CMN possessesvery high drug contents and exhibits a favorable GSH responsivenessfor disassembly. Subsequently, the released MR can trigger paraptosisto cause extensive vacuolization of ER and mitochondria, contributingto activating ICD for immunotherapy. Moreover, NLG919 would inhibitIDO to remodel the tumor microenvironment and promote the activationof cytotoxic T cells, leading to an intensive antitumor immunity.Abundant in vivo studies indicate that CMN is superiorin suppressing the proliferations of not only primary tumor but alsometastatic and rechallenged tumors. Such a GSH-responsive paraptosisinducer might provide a promising strategy to trigger ICD and enhancetumor immunotherapy.

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