Irradiated Microparticles Suppress Prostate Cancer by Tumor Microenvironment Reprogramming and Ferroptosis

Abstract

Abstract Immunogenic cell death (ICD) plays a crucial role in triggering the antitumor immune response in the tumor microenvironment (TME) through the release of damage-associated molecular patterns (DAMPs). Recently, considerable attention has been dedicated to ferroptosis, a type of ICD that is induced by intracellular iron and has been demonstrated to change the immune desert status of the TME. However, there remains significant room for improvement among strategies for inducing high levels of ICD through ferroptosis to fight cancers that are characterized by an immune desert, such as prostate cancer. Radiated tumor cell-derived microparticles (RMPs) are radiotherapy mimetics that have been shown to activate the cGAS-STING pathway, induce tumor cell ferroptosis, and inhibit M2 macrophage polarization. RMPs can also act as carriers of agents with remarkable biocompatibility. In the present study, we designed a therapeutic system wherein the ferroptosis inducer RSL-3 was loaded into RMPs to treat prostate cancer, which is considered a cold tumor, using in vitro and in vivo models involving RM-1 prostate carcinoma cells. Apoptosis inducer CT20 peptide (CT20p) was also added into the RMPs to aggravate ICD. In vitro experiments demonstrated that RSL-3- and CT20p-loaded RMPs (RC@RMPs) led to ferroptosis and apoptosis of RM-1 cells, and CT20p had a synergistic effect on ferroptosis by promoting ROS production and mitochondrial instability. RC@RMPs elevated the dendritic cell (DC) expression of MHCⅡ, CD80, and CD86 and facilitated M1 macrophage polarization. In a syngeneic mouse model of prostate cancer induced by RM-1 cells, RC@RMPs significantly inhibited tumor growth and prolonged survival time via DC activation, macrophage reprogramming, enhancement of CD8+ T cell presence, and proinflammatory cytokine production, without diffusing outside the tumor tissue. Moreover, combination treatment with anti-PD-1 showed improved effectiveness to inhibit RM-1 progression. This method provides a novel strategy for the synergistic enhancement of ICD for prostate cancer immunotherapies.