Nanoparticle delivery of miR-21-3p sensitizes melanoma to anti-PD-1 immunotherapy by promoting ferroptosis

Abstract

BackgroundAlthough anti-programmed cell death protein 1 (PD-1) immunotherapy is greatly effective in melanoma treatment, low response rate and treatment resistance significantly hinder its efficacy. Tumor cell ferroptosis triggered by interferon (IFN)-γ that is derived from tumor-infiltrating CD8+ T cells greatly contributes to the effect of immunotherapy. However, the molecular mechanism underlying IFN-γ-mediated ferroptosis and related potentially promising therapeutic strategy warrant further clarification. MicroRNAs (miRNAs) participate in ferroptosis execution and can be delivered systemically by multiple carriers, which have manifested obvious therapeutic effects on cancer.MethodsMiRNAs expression profile in IFN-γ-driven ferroptosis was obtained by RNA sequencing. Biochemical assays were used to clarify the role of miR-21-3p in IFN-γ-driven ferroptosis and the underlying mechanism. MiR-21-3p-loaded gold nanoparticles were constructed and systemically applied to analyze the role of miR-21-3p in anti-PD-1 immunotherapy in preclinical transplanted tumor model.ResultsMiRNAs expression profile of melanoma cells in IFN-γ-driven ferroptosis was first obtained. Then, upregulated miR-21-3p was proved to facilitate IFN-γ-mediated ferroptosis by potentiating lipid peroxidation. miR-21-3p increased the ferroptosis sensitivity by directly targeting thioredoxin reductase 1 (TXNRD1) to enhance lipid reactive oxygen species (ROS) generation. Furthermore, miR-21-3p overexpression in tumor synergized with anti-PD-1 antibody by promoting tumor cell ferroptosis. More importantly, miR-21-3p-loaded gold nanoparticles were constructed, and the systemic delivery of them increased the efficacy of anti-PD-1 antibody without prominent side effects in preclinical mice model. Ultimately, ATF3 was found to promote miR-21-3p transcription in IFN-γ-driven ferroptosis.ConclusionsMiR-21–3 p upregulation contributes to IFN-γ-driven ferroptosis and synergizes with anti-PD-1 antibody. Nanoparticle delivery of miR-21–3 p is a promising therapeutic approach to increase immunotherapy efficacy without obvious systemic side effects.

Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF

“…Therefore, the intervention of ferroptosis is promising in restraining melanoma progression and increasing the effectiveness of either targeted therapy or immunotherapy. Some studies have demonstrated the upstream regulatory mechanism of ferroptosis in melanoma before [ 14 , 15 , 16 ], and we previously reported that CAMKK2 and miR-21-3p were critical regulators of melanoma cell ferroptosis through the regulation of AMPK-Nrf2 and TXNRD1, respectively [ 8 , 49 ]. Herein, we proved that Wnt/β-catenin signaling was also implicated in melanoma cell ferroptosis, extending the upstream regulatory network of ferroptosis in melanoma.…”

“…Of note, two studies have highlighted that the induction of tumor cell ferroptosis triggered by IFN-γ resulting from infiltrated CD8 + T-cells mediates the influence of melanoma immunotherapy [ 12 , 13 ]. Our previous investigations proved that miR-21-3p and CAMKK2 regulated the TXNRD1 and AMPK-Nrf2 axes, respectively, to mediate the execution of melanoma cell ferroptosis [ 8 , 49 ]. Either nanoparticle delivery of miR-21-3p or systemic administration of a CAMKK2 inhibitor could prominently enhance the effectiveness of anti-PD-1 immunotherapy.…”

Relationship between miRNA and ferroptosis in tumors

“…In immunotherapy, IFN-γ is the main effector that triggers ferroptosis in tumor cells. Guo et al (2022) found that one of the important mechanisms for ferroptosis induced by IFN-γ in melanoma is the activation of the ATF3/ miR-21-3p/TXNRD1 axis, and blocking this axis attenuates ferroptosis and therapeutic effect of IFN-γ, which indicates that the overexpression of miR-21-3p may play a synergistic role with anti-PD-1 immunotherapy. In order to verify whether miR-21-3p can enhance the effect of anti-PD-1 in vivo, the researchers constructed miR-21-3p-loaded gold nanoparticles (miR-21-3p-AuNp), injected them into melanoma transplanted mice, and injected anti-PD-1 for immunotherapy.…”

From Molecular Mechanisms to Therapeutics: Understanding MicroRNA-21 in Cancer

“…This indicated that miR-21 could play a role in ferroptosis [ 93 ]. Interestingly, delivery of miR-21-3p to melanoma cell lines was found to promote interferon-gamma (IFN-γ)-mediated ferroptosis by targeting thioredoxin reductase 1 and elevating ROS generation [ 94 ].…”