Evoking tumor associated macrophages by mitochondria-targeted magnetothermal immunogenic cell death for cancer immunotherapy

Immunogenic cell death (ICD) based on endoplasmic reticulum (ER) stress has been widely studied as the fun-damentals of cancer immunotherapy. However, the currently available ICD inducers are still very rare and mostly highly toxic chemotherapeutic drugs. Herein, a novel ICD modality based on mitochondrial heat stress by magnetic hyperthermia treatment (MHT), is proposed for effectively evoking tumor-associated macrophages (TAMs) against cancer cells. A monodisperse and biocompatible nanomedicine by grafting arginyl-glycyl-aspartic acid (RGD) and (3-carboxypropyl)triphenylphosphonium bromide (TPP) onto the surface of superparamagnetic ZnCoFe2O4@ZnMnFe2O4 nanoparticles (MNPs), named as MNPs-RGD-TPP (MRT), was synthesized for mito-chondrial heat stress-induced oxidative damage of tumor cells under the magnetothermal manipulation. Such heat stress-damaged mitochondria can cause the immunogenic death of tumor cells to release damage-associated molecular patterns (DAMPs), including ATP and HSP 70, to M1-polarize TAMs, resulting in the reactivated immunoresponse of macrophages against cancer cells. The effectiveness and robustness of MRT nanomedicine in evoking TAMs-mediated extracellular killing or phagocytosis are verified both in vitro and in vivo. Such a ther-apeutic approach based on mitochondria-targeted magnetothermal ICD for activating TAMs may be instructive to future anticancer immunotherapy.

Automated summary

This study proposes a novel immunogenic cell death (ICD) modality based on mitochondrial heat stress by magnetic hyperthermia treatment (MHT), which effectively evokes tumor-associated macrophages (TAMs) against cancer cells. A nanomedicine named MRT is synthesized for mitochondria-targeted heat stress-induced oxidative damage of tumor cells, leading to the release of damage-associated molecular patterns (DAMPs) and the activation of TAMs-mediated immune response against cancer cells.