Semiconducting Polymer Nano-PROTACs for Activatable Photo-immunometabolic Cancer Therapy

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 19

PMID 34006860

Citations 62

Authors

Chi Zhang

Ziling Zeng

Dong Cui

Shasha He

Yuyan Jiang

Jingchao Li

Jiaguo Huang

Kanyi Pu

Affiliations

Soon will be listed here.

Abstract

Immunometabolic intervention has been applied to treat cancer via inhibition of certain enzymes associated with intratumoral metabolism. However, small-molecule inhibitors and genetic modification often suffer from insufficiency and off-target side effects. Proteolysis targeting chimeras (PROTACs) provide an alternative way to modulate protein homeostasis for cancer therapy; however, the always-on bioactivity of existing PROTACs potentially leads to uncontrollable protein degradation at non-target sites, limiting their in vivo therapeutic efficacy. We herein report a semiconducting polymer nano-PROTAC (SPN) with phototherapeutic and activatable protein degradation abilities for photo-immunometabolic cancer therapy. SPN can remotely generate singlet oxygen (O) under NIR photoirradiation to eradicate tumor cells and induce immunogenic cell death (ICD) to enhance tumor immunogenicity. Moreover, the PROTAC function of SPN is specifically activated by a cancer biomarker (cathepsin B) to trigger targeted proteolysis of immunosuppressive indoleamine 2,3-dioxygenase (IDO) in the tumor of living mice. The persistent IDO degradation blocks tryptophan (Trp)-catabolism program and promotes the activation of effector T cells. Such a SPNpro-mediated in-situ immunometabolic intervention synergizes immunogenic phototherapy to boost the antitumor T-cell immunity, effectively inhibiting tumor growth and metastasis. Thus, this study provides a polymer platform to advance PROTAC in cancer therapy.

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