cGAS-STING-activating nanoreactors with tumor-localized thrombosis- and lipid peroxidation-inducing capacity for combination cancer enzymes and immunotherapy

Abstract

The realization of tumor infarction therapy through the induction of tumor-localized thrombosis is an appealing cancer treatment strategy, but its therapeutic potency is severely hindered by posttreatment tumor relapse, which mainly results from incomplete intravascular thrombosis. Herein, a pH-responsive nanoreactor (coined as TLCaP₂ NRs) is designed by enveloping thrombin and lipoxygenase within poly(ethylene glycol)-b-poly(glutamic acid) copolymeric micelles through the biomineralization growth of calcium phosphate. Thrombin is adopted to occupy tumor blood vessels through inducing intravascular blood clots, the polyunsaturated fatty acids of which are synergistically converted to cytotoxic lipid radicals by lipoxygenase and the released hemoglobin to induce ferroptotic cancer cell death. Upon tumor accumulation, TLCaP₂ NRs could inhibit the growth of both CT26 and H22 tumors in mice through the enzymatic promotion of tumor-localized intravascular thrombosis and lipid peroxidation. Moreover, via the doping of Mn²⁺, which can activate the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, the yielded TLCaMnP₂ NRs showed potent tumor suppression efficacy through the enzymatic induction of cancer cell death and the elicitation of antitumor immunity. This work highlights an ingenious strategy to prepare immunogenic nanoreactors via a biomineralization process for the enzymatic induction of intravascular thrombosis and lipid peroxidation and the priming of antitumor immunity.