PT  - JOURNAL ARTICLE
AU  - Weinan Guo
AU  - Zhenjie Wu
AU  - Jianru Chen
AU  - Sen Guo
AU  - Weiming You
AU  - Sijia Wang
AU  - Jinyuan Ma
AU  - Huina Wang
AU  - Xiangxu Wang
AU  - Hao Wang
AU  - Jingjing Ma
AU  - Yuqi Yang
AU  - Yangzi Tian
AU  - Qiong Shi
AU  - Tianwen Gao
AU  - Xiuli Yi
AU  - Chunying Li
TI  - Nanoparticle delivery of miR-21-3p sensitizes melanoma to anti-PD-1 immunotherapy by promoting ferroptosis
AID  - 10.1136/jitc-2021-004381
DP  - 2022 Jun 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e004381
VI  - 10
IP  - 6
4099  - http://jitc.bmj.com/content/10/6/e004381.short
4100  - http://jitc.bmj.com/content/10/6/e004381.full
SO  - J Immunother Cancer2022 Jun 01; 10
AB  - Background Although 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.Methods MiRNAs 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.Results MiRNAs 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.Conclusions MiR-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.Sequencing data is accessible through GEO series accession numbers GSE186497. Source data for Figures are available from the corresponding authors upon request.