Self-delivery oxidative stress amplifier for chemotherapy sensitized immunotherapy

Abstract

Amplifying oxidative stress to break intracellular redox homeostasis could accelerate tumor cell death. In this work, a self-delivery oxidative stress amplifier is developed for chemotherapy sensitized immunotherapy. By virtue of the π-π stacking and coordination effect, copper ions (Cu²⁺), doxorubicin (DOX) and NLG919 are able to self-assembly into the nanosized oxidative stress amplifier (designated as Cu-DON) with a favorable stability and a biocompatibility. Intravenously administrated Cu-DON could effectively accumulate and penetrate into tumor tissues for cellular uptake. Subsequently, the GSH-responsive DOX release will initiate the immunogenic chemotherapy (IC) for primary tumor inhibition. Moreover, Cu²⁺-mediated GSH consumption and DOX-triggered oxidative stress could cause the intracellular redox imbalance, contributing to immunogenic cell death (ICD) response. Further, the concomitant release of NLG919 would inhibit indoleamine 2,3-dioxygenase 1 (IDO-1) to reverse immunosuppressive tumor microenvironment (ITM) for enhanced immunotherapy. Consequently, this self-delivery oxidative stress amplifier greatly restrains the growth of primary, distant as well as rechallenged tumors by chemotherapy sensitized immunotherapy, which would shed light on the development of combination therapy to block tumor growth and metastasis in clinic.

Keywords: Chemotherapy; Immunogenic cell death; Immunotherapy; Oxidative stress; Self-delivery.