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 fundamentals 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 mitochondrial 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 therapeutic approach based on mitochondria-targeted magnetothermal ICD for activating TAMs may be instructive to future anticancer immunotherapy.