Targeting Ferroptosis Pathway to Combat Therapy Resistance and Metastasis of Cancer

Abstract

Ferroptosis is an iron-dependent regulated form of cell death caused by excessive lipid peroxidation. This form of cell death differed from known forms of cell death in morphological and biochemical features such as apoptosis, necrosis, and autophagy. Cancer cells require higher levels of iron to survive, which makes them highly susceptible to ferroptosis. Therefore, it was found to be closely related to the progression, treatment response, and metastasis of various cancer types. Numerous studies have found that the ferroptosis pathway is closely related to drug resistance and metastasis of cancer. Some cancer cells reduce their susceptibility to ferroptosis by downregulating the ferroptosis pathway, resulting in resistance to anticancer therapy. Induction of ferroptosis restores the sensitivity of drug-resistant cancer cells to standard treatments. Cancer cells that are resistant to conventional therapies or have a high propensity to metastasize might be particularly susceptible to ferroptosis. Some biological processes and cellular components, such as epithelial-mesenchymal transition (EMT) and noncoding RNAs, can influence cancer metastasis by regulating ferroptosis. Therefore, targeting ferroptosis may help suppress cancer metastasis. Those progresses revealed the importance of ferroptosis in cancer, In order to provide the detailed molecular mechanisms of ferroptosis in regulating therapy resistance and metastasis and strategies to overcome these barriers are not fully understood, we described the key molecular mechanisms of ferroptosis and its interaction with signaling pathways related to therapy resistance and metastasis. Furthermore, we summarized strategies for reversing resistance to targeted therapy, chemotherapy, radiotherapy, and immunotherapy and inhibiting cancer metastasis by modulating ferroptosis. Understanding the comprehensive regulatory mechanisms and signaling pathways of ferroptosis in cancer can provide new insights to enhance the efficacy of anticancer drugs, overcome drug resistance, and inhibit cancer metastasis.

Keywords: cancer; drug resistance; ferroptosis; metastasis; peroxidation.

FIGURE 1

Mechanism underlying the occurrence and regulation of ferroptosis. (1) Ferroptosis is mainly caused by lipid peroxidation. ROS leading to ferroptosis are produced by the iron-dependent Fenton reaction, mitochondrial electron transport chain or NOX proteins. Ferroptosis can be triggered by enhancing the synthesis of lipid ROS. (2) Inhibition of SLC7A11 deprives cells of cysteine, resulting in the loss of GSH and inactivation of GPX4. The latter further leads to the accumulation of lipid ROS and ferroptosis. The tricarboxylic acid cycle (TCA cycle) and electron carriers (ETC) in mitochondria stimulate GSH deficiency, thus leading to ferroptosis. The release of Fe²⁺ in mitochondria increases the level of free Fe²⁺ in cells and eventually promotes the production of lipid ROS. Lysosomal ROS contribute to the production of lipid ROS. In lysosomes, STAT3-mediated expression of cathepsin B is essential for ferroptosis via the MEK-ERK signaling pathway. In the Golgi apparatus, the Golgi stress response can inhibit ARF1, which is an inhibitor of GSH and ACSL4 and an activator of SLC7A11. Silencing ARF1 promotes ferroptosis by increasing cellular ROS levels.

FIGURE 2

Reversing resistance or enhancing the efficacy of targeted therapy and chemotherapy by targeting the ferroptosis pathway. (A) Targeted drugs exert antitumor effects by blocking oncogenic signaling pathways, but innate or acquired resistance reduces their efficacy. (B) One of the mechanisms of resistance is reduced susceptibility to ferroptosis. Targeting multiple pathways in ferroptosis to restore their response to ferroptosis could eliminate resistance or improve the efficacy of existing standard treatments, including chemotherapy and targeted therapy. System Xc⁻ and GPX4 have critical roles in preventing ferroptosis and potential targets to reverse treatment resistance. Other factors that regulate the redox of intracellular lipid are also have critical roles in anticancer treatment resistance. Many approved drugs target those potential targets and may reverse the resistance by exploiting ferroptosis pathway.

FIGURE 3

Reversal of radioresistance by targeting ferroptosis. Radioresistance remains a major factor in radiotherapy failure. Radiation therapy can lead to the production of massive ROS and upregulate the expression of ACSL4, promote lipid peroxidation and eventually cause ferroptosis. However, radiotherapy also induced an adaptive response in tumor cells. The expression of ferroptosis suppressors, including SLC7A11 and GPX4, was also significantly upregulated, which promoted cancer cell survival and radioresistance after radiotherapy. FINs that inhibit SLC7A11 or GPX4 can enhance the sensitivity of radioresistant cancer cells to IR-induced ferroptosis and reverse radioresistance. miR-7-5p controls radioresistance via ROS generation that leads to ferroptosis. Knockdown of miR-7-5p increased ROS and reversed radioresistance.

FIGURE 4

Targeting the ferroptosis pathway in immune cells or cancer cells reverses immunotherapy resistance or enhances therapeutic efficacy. (A) The ferroptosis signaling pathway in immune cells regulates antitumor immune function. Gpx4 protects activated Treg cells from lipid peroxidation and ferroptosis. Loss of Gpx4 leads to excessive accumulation of lipid peroxides and ferroptosis of Treg cells after TCR/CD28 co-stimulation. Gpx4-deficient Treg cells upregulate the production of IL-1β and TH17 responses, increasing the number and killing activity of intratumoral CD8⁺ T cells. Knockdown of Gpx4 in Treg cells inhibited tumor growth and simultaneously enhanced antitumor immunity. (B) TYRO3 expressed by tumor cells leads to resistance to anti-PD-1/PD-L1 therapy by inhibiting tumor ferroptosis. Some molecules produced by apoptotic cells in the tumor microenvironment activate the AKT/NRF2 axis after binding to TYRO3, thereby promoting the transcription of ferroptosis-inducing genes and inhibiting the expression of ferroptosis-inducing genes, leading to anti-PD-1/PD-L1 therapy resistance. Inhibition of TYRO3 promotes tumor ferroptosis and sensitizes resistant tumors to anti-PD-1 therapy. (C,D) CD8⁺ T cell-derived IFN-γ in the tumor microenvironment promotes lipid peroxidation and ferroptosis in tumor cells. Drugs that promote ferroptosis enhance the antitumor efficacy of immunotherapy. (C) IFN-γ promotes lipid peroxidation and ferroptosis in tumor cells by inhibiting the expression of SLC3A2 and SLC7A11. (D) IFN-γ activates the JAK/STAT1 signaling pathway in tumor cells, which in turn promotes the expression of ACSL4 through interferon regulatory factor 1 (IRF1). Supplementation with low-dose AA promotes ferroptosis in tumor cells and enhances the antitumor activity of checkpoint therapy.

FIGURE 5

Ferroptosis and cancer metastasis. (1) Various changes in the E-cadherin-Merlin-Hippo-YAP axis are associated with ferroptosis. When E-cadherin, Merlin, and Hippo are inhibited, YAP is activated to further induce ferroptosis, while NF2/Merlin Deficiency drives cancer metastasis. (2) EMT is favorable to the survival of cancer cells and metastasis, which blocks E-cadherin-induced cell–cell interactions and activates YAP, thus leading to ferroptosis. MTDH contributes to ferroptosis by reducing intracellular GSH levels by downregulating GPX4 and SLC3A2. (3) HIF has a dual role in regulating ferroptosis in cancer cells. Activated HIF-2α upregulates lipid and iron-regulated genes and enhances lipid peroxidation of PUFAs, thus enhancing their sensitivity to ferroptosis. In contrast, it prevents ferroptosis in cancer cells by improving the cellular uptake of fatty acids and lipid storage by upregulating FABP3 and FABP7.