Microenvironment immune response induced by tumor ferroptosis-the application of nanomedicine

Tian Yun, Zhenzhu Liu, Jianbo Wang, Rui Wang, Liang Zhu, Zheng Zhu, Xuejian Wang, Tian Yun, Zhenzhu Liu, Jianbo Wang, Rui Wang, Liang Zhu, Zheng Zhu, Xuejian Wang

Abstract

Ferroptosis is a non-apoptotic regulatory form of cell death that has sparked significant interest and research in cancer treatment and certain small chemical inducers have been used in the clinic. These inducers's weak water solubility, poor targeting, rapid metabolism; and other undesirable characteristics; however, for therapeutic approaches that combine immunotherapy and ferroptosis, challenges such as medication delivery, the complexity of the tumor microenvironment, and immunosuppression remain. The targeted, low toxicity, and efficient distribution benefits of nanotechnology have considerably enhanced the therapeutic efficacy of combining immunotherapy with ferroptosis. This paper describes the distinct mechanism of ferroptosis in tumor therapy and immunotherapy, as well as the application and benefits of nanotechnology in the combination of tumor immunotherapy and ferroptosis.

Systematic review registration: https://ichgcp.net/clinical-trials-registry/NCT00941070" title="See in ClinicalTrials.gov">NCT00941070.

Keywords: cancer therapy; ferroptosis; immunity therapy; nanotechnology; tumor microenvironment.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Yun, Liu, Wang, Wang, Zhu, Zhu and Wang.

Figures

Figure 1
Figure 1
The primary mechanism of ferroptosis. Extracellular Fe3+ binds to transferrin receptor 1 (Tfr1) to form Fe2+; Fe2+ forms an unstable iron pool in the presence of divalent metal transporter 1 (DMT1). The Fenton reaction generates lipid reactive oxygen species (ROS), which cause cell membrane breakdown and, in the end, ferroptosis. The Xc- system, comprised of Recombinant Solute Carrier Family 3 (SLC7A11) and Recombinant Solute Carrier Family 7, Member 11 (SLC3A2), transports internal glutamate to the cell’s surface while also importing cystine, which initiates glutathione synthesis. Glutathione peroxidase 4 (GPX4) is a glutathione substrate that inhibits ROS and ferroptosis.
Figure 2
Figure 2
Ferroptosis plays a variety of roles in the tumor microenvironment (TME). CD8+ T cells in the TME have been shown to secrete IFNγ, which inhibits SLC3A2 and SLC7A11, promotes tumor cell ferroptosis, and improves antitumor immunity. High fatty acid levels in the TME, on the other hand, enhance CD36 upregulation, trigger ferroptosis in CD8+ T cells, and hasten tumor growth. Depletion of GPX4 in tumor-associated macrophages (TAMs) can reduce M2-type macrophage survival while increasing antitumor immunity without changing the amount of M1-type macrophages. KRAS-G12D is released pancreatic cells undergo ferroptosis, promoting the transition of macrophages into M2 type and tumor development.
Figure 3
Figure 3
To improve tumor therapy, nanoparticles are used in ferroptosis and tumor immunity. Nanoparticles inside tumors can promote ferroptosis in tumor cells by releasing significant levels of Fe2+ or suppressing System Xc-, allowing them to penetrate solid tumors through enhanced permeability and retention (EPR). Nanoparticles can also convert M2-type cells to M1-type cells inside tumors, improve immunogenic cell death (ICD), and promote DC cell maturation, all of which improve anti-tumor immunity. To improve tumor therapy, nanoparticles can trigger ferroptosis while also increasing antitumor immunity in solid tumors. DAMPs, Damage associated molecular patterns.

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