Abstract
Reactive oxygen species (ROS) in biological systems are transient but essential molecules that are generated and eliminated by a complex set of delicately balanced molecular machineries. Disruption of redox homeostasis has been associated with various human diseases, especially cancer, in which increased ROS levels are thought to have a major role in tumour development and progression. As such, modulation of cellular redox status by targeting ROS and their regulatory machineries is considered a promising therapeutic strategy for cancer treatment. Recently, there has been major progress in this field, including the discovery of novel redox signalling pathways that affect the metabolism of tumour cells as well as immune cells in the tumour microenvironment, and the intriguing ROS regulation of biomolecular phase separation. Progress has also been made in exploring redox regulation in cancer stem cells, the role of ROS in determining cell fate and new anticancer agents that target ROS. This Review discusses these research developments and their implications for cancer therapy and drug discovery, as well as emerging concepts, paradoxes and future perspectives.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Halliwell, B. Reactive oxygen species (ROS), oxygen radicals and antioxidants: where are we now, where is the field going and where should we go? Biochem. Biophys. Res. Commun. 633, 17–19 (2022).
Sies, H. et al. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nat. Rev. Mol. Cell Biol. 23, 499–515 (2022).
Trachootham, D., Lu, W., Ogasawara, M. A., Nilsa, R. D. & Huang, P. Redox regulation of cell survival. Antioxid. Redox Signal. 10, 1343–1374 (2008).
Gorrini, C., Harris, I. S. & Mak, T. W. Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 12, 931–947 (2013).
Trachootham, D., Alexandre, J. & Huang, P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat. Rev. Drug Discov. 8, 579–591 (2009).
Behring, J. B. et al. Spatial and temporal alterations in protein structure by EGF regulate cryptic cysteine oxidation. Sci. Signal. 13, eaay7315 (2020).
El Banna, N. et al. Redox modifications of cysteine-containing proteins, cell cycle arrest and translation inhibition: involvement in vitamin C-induced breast cancer cell death. Redox Biol. 26, 101290 (2019).
Gibhardt, C. S. et al. Oxidative stress-induced STIM2 cysteine modifications suppress store-operated calcium entry. Cell Rep. 33, 108292 (2020).
Halvey, P. J. et al. Selective oxidative stress in cell nuclei by nuclear-targeted D-amino acid oxidase. Antioxid. Redox Signal. 9, 807–816 (2007).
Putker, M. et al. Redox-dependent control of FOXO/DAF-16 by transportin-1. Mol. Cell 49, 730–742 (2013).
DeBlasi, J. M. & DeNicola, G. M. Dissecting the crosstalk between NRF2 signaling and metabolic processes in cancer. Cancers 12, 3023 (2020).
Forman, H. J., Zhang, H. & Rinna, A. Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol. Asp. Med. 30, 1–12 (2009).
Matsui, R. et al. Redox regulation via glutaredoxin-1 and protein S-glutathionylation. Antioxid. Redox Signal. 32, 677–700 (2020).
Guo, Y. et al. Oxidative stress-induced FABP5 S-glutathionylation protects against acute lung injury by suppressing inflammation in macrophages. Nat. Commun. 12, 7094 (2021).
Liang, X. et al. Characterization of methionine oxidation and methionine sulfoxide reduction using methionine-rich cysteine-free proteins. BMC Biochem. 13, 21 (2012).
He, D. et al. Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis. Mol. Cell 82, 3045–3060 (2022). This article presents important evidence that PKM2 methionine oxidation functions as a reversible redox switch that regulates tumour metastasis.
Raman, D., Chong, S. J. F., Iskandar, K., Hirpara, J. L. & Pervaiz, S. Peroxynitrite promotes serine-62 phosphorylation-dependent stabilization of the oncoprotein c-Myc. Redox Biol. 34, 101587 (2020).
Chong, S. J. F. et al. Serine-70 phosphorylated Bcl-2 prevents oxidative stress-induced DNA damage by modulating the mitochondrial redox metabolism. Nucleic Acids Res. 48, 12727–12745 (2020).
Low, I. C., Loh, T., Huang, Y., Virshup, D. M. & Pervaiz, S. Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity. Blood 124, 2223–2234 (2014).
Yee, Y. H., Chong, S. J. F., Kong, L. R., Goh, B. C. & Pervaiz, S. Sustained IKKβ phosphorylation and NF-κB activation by superoxide-induced peroxynitrite-mediated nitrotyrosine modification of B56γ3 and PP2A inactivation. Redox Biol. 41, 101834 (2021).
Karin, M. & Lin, A. NF-κB at the crossroads of life and death. Nat. Immunol. 3, 221–227 (2002).
Chen, F. et al. Extracellular vesicle-packaged HIF-1α-stabilizing lncRNA from tumour-associated macrophages regulates aerobic glycolysis of breast cancer cells. Nat. Cell Biol. 21, 498–510 (2019).
He, X. Y. et al. LncRNA modulates Hippo-YAP signaling to reprogram iron metabolism. Nat. Commun. 14, 2253 (2023).
Gao, J. et al. LncRNA DINOR is a virulence factor and global regulator of stress responses in Candida auris. Nat. Microbiol. 6, 842–851 (2021).
He, W. et al. MSC-regulated lncRNA MACC1-AS1 promotes stemness and chemoresistance through fatty acid oxidation in gastric cancer. Oncogene 38, 4637–4654 (2019).
Adriaens, C. et al. p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity. Nat. Med. 22, 861–868 (2016).
Zhang, B. et al. LncRNA HEPFAL accelerates ferroptosis in hepatocellular carcinoma by regulating SLC7A11 ubiquitination. Cell Death Dis. 13, 734 (2022).
Wang, Y. et al. NSUN2 alleviates doxorubicin-induced myocardial injury through Nrf2-mediated antioxidant stress. Cell Death Discov. 9, 43 (2023).
Liu, S., Qiu, Y., Xiang, R. & Huang, P. Characterization of H2O2-induced alterations in global transcription of mRNA and lncRNA. Antioxidants 11, 495 (2022). This study shows the regulation of global transcription of mRNA and lncRNA by hydrogen peroxide in normal and cancer cells.
Ashouri, A. et al. Pan-cancer transcriptomic analysis associates long non-coding RNAs with key mutational driver events. Nat. Commun. 7, 13197 (2016).
Ji, Z., Song, R., Regev, A. & Struhl, K. Many lncRNAs, 5′UTRs, and pseudogenes are translated and some are likely to express functional proteins. eLife 4, e08890 (2015).
Sudmant, P. H., Lee, H., Dominguez, D., Heiman, M. & Burge, C. B. Widespread accumulation of ribosome-associated isolated 3′ UTRs in neuronal cell populations of the aging brain. Cell Rep. 25, 2447–2456 (2018).
Lee, S. H. et al. Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia. Nature 561, 127–131 (2018).
Kesner, J. S. et al. Noncoding translation mitigation. Nature 617, 395–402 (2023).
Colussi, C. et al. HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment. Proc. Natl Acad. Sci. USA 105, 19183–19187 (2008).
Li, W. et al. Nuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation. Nat. Commun. 13, 7414 (2022).
de Luca, A. et al. Treatment of doxorubicin-resistant MCF7/Dx cells with nitric oxide causes histone glutathionylation and reversal of drug resistance. Biochem. J. 440, 175–183 (2011).
Garcia-Gimenez, J. L. et al. Histone H3 glutathionylation in proliferating mammalian cells destabilizes nucleosomal structure. Antioxid. Redox Signal. 19, 1305–1320 (2013).
Mosharov, E., Cranford, M. R. & Banerjee, R. The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes. Biochemistry 39, 13005–13011 (2000).
Ying, Z. et al. Short-term mitochondrial permeability transition pore opening modulates histone lysine methylation at the early phase of somatic cell reprogramming. Cell Metab. 28, 935–945.e5 (2018).
O’Hagan, H. M. et al. Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands. Cancer Cell 20, 606–619 (2011).
Hahm, J. Y., Park, J., Jang, E. S. & Chi, S. W. 8-Oxoguanine: from oxidative damage to epigenetic and epitranscriptional modification. Exp. Mol. Med. 54, 1626–1642 (2022).
de Miguel, F. J. et al. Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer. Cancer Cell 41, 1516–1534 (2023).
Chen, H., Zhao, T., Sun, D., Wu, M. & Zhang, Z. Changes of RNA N6-methyladenosine in the hormesis effect induced by arsenite on human keratinocyte cells. Toxicol. In Vitro 56, 84–92 (2019).
Yu, F. et al. Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response. Nucleic Acids Res. 49, 5779–5797 (2021).
Liu, X. et al. Adenylate kinase 4 modulates the resistance of breast cancer cells to tamoxifen through an m6A-based epitranscriptomic mechanism. Mol. Ther. 28, 2593–2604 (2020).
Tanaka, M. & Chock, P. B. Oxidative modifications of RNA and its potential roles in biosystem. Front. Mol. Biosci. 8, 685331 (2021).
Bartman, C. R. et al. Slow TCA flux and ATP production in primary solid tumours but not metastases. Nature 614, 349–357 (2023). This article provides in vivo evidence for different mitochondrial metabolic activity and ROS generation between primary and metastatic cancer cells.
Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).
Anastasiou, D. et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334, 1278–1283 (2011).
Maller, C., Schroder, E. & Eaton, P. Glyceraldehyde 3-phosphate dehydrogenase is unlikely to mediate hydrogen peroxide signaling: studies with a novel anti-dimedone sulfenic acid antibody. Antioxid. Redox Signal. 14, 49–60 (2011).
Liu, X. et al. Mitochondrial TXNRD3 confers drug resistance via redox-mediated mechanism and is a potential therapeutic target in vivo. Redox Biol. 36, 101652 (2020).
Marinho, H. S., Real, C., Cyrne, L., Soares, H. & Antunes, F. Hydrogen peroxide sensing, signaling and regulation of transcription factors. Redox Biol. 2, 535–562 (2014).
Semenza, G. L., Roth, P. H., Fang, H. M. & Wang, G. L. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J. Biol. Chem. 269, 23757–23763 (1994).
Liu, B. et al. Hepatitis B virus stimulates G6PD expression through HBx-mediated Nrf2 activation. Cell Death Dis. 6, e1980 (2015).
Aykin-Burns, N., Ahmad, I. M., Zhu, Y., Oberley, L. W. & Spitz, D. R. Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation. Biochem. J. 418, 29–37 (2009).
Li, L., Fath, M. A., Scarbrough, P. M., Watson, W. H. & Spitz, D. R. Combined inhibition of glycolysis, the pentose cycle, and thioredoxin metabolism selectively increases cytotoxicity and oxidative stress in human breast and prostate cancer. Redox Biol. 4, 127–135 (2015). This article provides evidence for uncontrolled glucose consumption in cancer cells to generate reducing equivalents to detoxify ROS as a metabolic vulnerability for antitumour therapy.
Wang, J. B. et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18, 207–219 (2010).
Qiao, S. et al. Wild-type IDH2 protects nuclear DNA from oxidative damage and is a potential therapeutic target in colorectal cancer. Oncogene 40, 5880–5892 (2021).
Liu, R. et al. Malignant transformation by oncogenic K-ras requires IDH2-mediated reductive carboxylation to promote glutamine utilization. Cancer Commun. 43, 285–289 (2023).
Zeng, P. et al. Reductive TCA cycle catalyzed by wild-type IDH2 promotes acute myeloid leukemia and is a metabolic vulnerability for potential targeted therapy. J. Hematol. Oncol. 15, 30 (2022).
Hausladen, A. & Fridovich, I. Superoxide and peroxynitrite inactivate aconitases, but nitric oxide does not. J. Biol. Chem. 269, 29405–29408 (1994).
Andersson, U., Leighton, B., Young, M. E., Blomstrand, E. & Newsholme, E. A. Inactivation of aconitase and oxoglutarate dehydrogenase in skeletal muscle in vitro by superoxide anions and/or nitric oxide. Biochem. Biophys. Res. Commun. 249, 512–516 (1998).
Oberley, L. W., Oberley, T. D. & Buettner, G. R. Cell division in normal and transformed cells: the possible role of superoxide and hydrogen peroxide. Med. Hypotheses 7, 21–42 (1981).
Church, S. L. et al. Increased manganese superoxide dismutase expression suppresses the malignant phenotype of human melanoma cells. Proc. Natl Acad. Sci. USA 90, 3113–3117 (1993).
Chiu, H. Y., Tay, E. X. Y., Ong, D. S. T. & Taneja, R. Mitochondrial dysfunction at the center of cancer therapy. Antioxid. Redox Signal. 32, 309–330 (2020).
Li, X. et al. A CCL2/ROS autoregulation loop is critical for cancer-associated fibroblasts-enhanced tumor growth of oral squamous cell carcinoma. Carcinogenesis 35, 1362–1370 (2014).
Williams, D. H., Jeffery, L. J. & Murray, E. J. Aurothioglucose inhibits induced NF-kB and AP-1 activity by acting as an IL-1 functional antagonist. Biochim. Biophys. Acta 1180, 9–14 (1992).
Hamarsheh, S. et al. Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation. Nat. Commun. 11, 1659 (2020).
Li, Z. et al. Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression. Nat. Commun. 13, 6239 (2022).
Zhong, Z. et al. TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat. Commun. 4, 1611 (2013).
Ball, D. P. et al. Oxidized thioredoxin-1 restrains the NLRP1 inflammasome. Sci. Immunol. 7, eabm7200 (2022).
Blaser, H., Dostert, C., Mak, T. W. & Brenner, D. TNF and ROS crosstalk in inflammation. Trends Cell Biol. 26, 249–261 (2016).
Ridker, P. M. et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 390, 1833–1842 (2017).
Allen, I. C. et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J. Exp. Med. 207, 1045–1056 (2010).
Beharka, A. A., Wu, D., Serafini, M. & Meydani, S. N. Mechanism of vitamin E inhibition of cyclooxygenase activity in macrophages from old mice: role of peroxynitrite. Free Radic. Biol. Med. 32, 503–511 (2002).
Singh, A. et al. NADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Toll-like receptor-4. Sci. Rep. 7, 14346 (2017).
Muri, J. et al. Cyclopentenone prostaglandins and structurally related oxidized lipid species instigate and share distinct pro- and anti-inflammatory pathways. Cell Rep. 30, 4399–4417 (2020).
Narunsky-Haziza, L. et al. Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions. Cell 185, 3789–3806.e17 (2022).
Liu, Y. et al. Bacterial genotoxin accelerates transient infection-driven murine colon tumorigenesis. Cancer Discov. 12, 236–249 (2022).
Goodwin, A. C. et al. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc. Natl Acad. Sci. USA 108, 15354–15359 (2011).
Buck, M. & Chojkier, M. Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants. EMBO J. 15, 1753–1765 (1996).
Brown, J. L. et al. Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice. J. Cachexia Sarcopenia Muscle 8, 926–938 (2017).
Choi, S. et al. Skeletal muscle-specific Prmt1 deletion causes muscle atrophy via deregulation of the PRMT6-FOXO3 axis. Autophagy 15, 1069–1081 (2019).
Wyke, S. M. & Tisdale, M. J. NF-κB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin-proteasome system in skeletal muscle. Br. J. Cancer 92, 711–721 (2005).
Leduc-Gaudet, J. P. et al. MYTHO is a novel regulator of skeletal muscle autophagy and integrity. Nat. Commun. 14, 1199 (2023).
Assi, M., Derbre, F., Lefeuvre-Orfila, L. & Rebillard, A. Antioxidant supplementation accelerates cachexia development by promoting tumor growth in C26 tumor-bearing mice. Free Radic. Biol. Med. 91, 204–214 (2016).
Assi, M. & Rébillard, A. The Janus-faced role of antioxidants in cancer cachexia: new insights on the established concepts. Oxid. Med. Cell. Longev. 2016, 9579868 (2016).
Ballarò, R. et al. Moderate exercise improves experimental cancer cachexia by modulating the redox homeostasis. Cancers 11, 285 (2019).
Duwe, A. K., Werkmeister, J., Roder, J. C., Lauzon, R. & Payne, U. Natural killer cell-mediated lysis involves an hydroxyl radical-dependent step. J. Immunol. 134, 2637–2644 (1985).
Iyer, G. Y. N., Islam, M. F. & Quastel, J. H. Biochemical aspects of phagocytosis. Nature 192, 535–541 (1961).
Morad, H., Luqman, S., Tan, C. H., Swann, V. & McNaughton, P. A. TRPM2 ion channels steer neutrophils towards a source of hydrogen peroxide. Sci. Rep. 11, 9339 (2021).
Savina, A. et al. NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. Cell 126, 205–218 (2006).
Shen, K. et al. Exosomes from adipose-derived stem cells alleviate the inflammation and oxidative stress via regulating Nrf2/HO-1 axis in macrophages. Free Radic. Biol. Med. 165, 54–66 (2021).
Jackson, S. H., Devadas, S., Kwon, J., Pinto, L. A. & Williams, M. S. T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation. Nat. Immunol. 5, 818–827 (2004).
Sena, L. A. et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38, 225–236 (2013). This article reveals that mitochondrial metabolism is a critical component of T cell activation to produce ROS to activate NFAT and lead to IL-2 secretion.
Zhang, H. et al. Sustained AhR activity programs memory fate of early effector CD8+ T cells. Proc. Natl Acad. Sci. USA 121, e2317658121 (2024).
Matata, B. M. & Galiñanes, M. Peroxynitrite is an essential component of cytokines production mechanism in human monocytes through modulation of nuclear factor-κB DNA binding activity. J. Biol. Chem. 277, 2330–2335 (2002).
Yang, R. et al. Hydrogen sulfide promotes Tet1- and Tet2-mediated Foxp3 demethylation to drive regulatory T cell differentiation and maintain immune homeostasis. Immunity 43, 251–263 (2015).
Corzo, C. A. et al. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J. Immunol. 182, 5693–5701 (2009).
Tcyganov, E. N. et al. Peroxynitrite in the tumor microenvironment changes the profile of antigens allowing escape from cancer immunotherapy. Cancer Cell 40, 1173–1189 (2022). This work details the role of peroxynitrite in causing changes of tumour antigens leading to resistance to immunotherapy.
Nagaraj, S. et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat. Med. 13, 828–835 (2007).
Molon, B. et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J. Exp. Med. 208, 1949–1962 (2011).
Chougnet, C. A. et al. Loss of phagocytic and antigen cross-presenting capacity in aging dendritic cells is associated with mitochondrial dysfunction. J. Immunol. 195, 2624–2632 (2015).
Scharping, N. E. et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat. Immunol. 22, 205–215 (2021). This article shows the role of mitochondrial ROS in mediating T cell exhaustion.
Izawa, S. et al. H2O2 production within tumor microenvironment inversely correlated with infiltration of CD56dim NK cells in gastric and esophageal cancer: possible mechanisms of NK cell dysfunction. Cancer Immunol. Immunother. 60, 1801–1810 (2011).
Muri, J. & Kopf, M. Redox regulation of immunometabolism. Nat. Rev. Immunol. 21, 363–381 (2021).
Takahashi, A. et al. Preferential cell death of CD8+ effector memory (CCR7−CD45RA−) T cells by hydrogen peroxide-induced oxidative stress. J. Immunol. 174, 6080–6087 (2005).
Arensman, M. D. et al. Cystine–glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity. Proc. Natl Acad. Sci. USA 116, 9533–9542 (2019).
Muri, J. et al. The thioredoxin-1 system is essential for fueling DNA synthesis during T-cell metabolic reprogramming and proliferation. Nat. Commun. 9, 1851 (2018).
Yue, T. et al. SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell-mediated immunity. Science 372, eaba4220 (2021).
Beury, D. W. et al. Myeloid-derived suppressor cell survival and function are regulated by the transcription factor Nrf2. J. Immunol. 196, 3470–3478 (2016).
Griess, B., Mir, S., Datta, K. & Teoh-Fitzgerald, M. Scavenging reactive oxygen species selectively inhibits M2 macrophage polarization and their pro-tumorigenic function in part, via Stat3 suppression. Free Radic. Biol. Med. 147, 48–60 (2020).
Mougiakakos, D., Johansson, C. C. & Kiessling, R. Naturally occurring regulatory T cells show reduced sensitivity toward oxidative stress-induced cell death. Blood 113, 3542–3545 (2009).
Glorieux, C. et al. Regulation of PD-L1 expression in K-ras-driven cancers through ROS-mediated FGFR1 signaling. Redox Biol. 38, 101780 (2021). This article reports the role of ROS in the activation of immune checkpoint and reveals the underlying mechanisms.
Zhang, W. et al. Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. Nat. Cell Biol. 14, 276–286 (2012).
Wang, W. et al. Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell 165, 1092–1105 (2016). This study shows a complex redox-mediated interplay between stroma, immune cells and cancer cells.
Badgley, M. A. et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 368, 85–89 (2020).
Kidwell, C. U. et al. Transferred mitochondria accumulate reactive oxygen species, promoting proliferation. eLife 12, e85494 (2023).
Xu, S. et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity 54, 1561–1577 (2021).
Hicks, K. C., Tyurina, Y. Y., Kagan, V. E. & Gabrilovich, D. I. Myeloid cell-derived oxidized lipids and regulation of the tumor microenvironment. Cancer Res. 82, 187–194 (2022).
Glorieux, C. et al. Cisplatin and gemcitabine exert opposite effects on immunotherapy with PD-1 antibody in K-ras-driven cancer. J. Adv. Res. 40, 109–124 (2022).
Glorieux, C., Cui, L., Zeng, P., Xia, X. & Huang, P. Diverse effects of chemotherapeutic agents on immune cell function and implications in immunochemotherapy. Cancer Commun. 41, 432–435 (2021).
Kalyanaraman, B. NAC, NAC, Knockin’ on Heaven’s door: interpreting the mechanism of action of N-acetylcysteine in tumor and immune cells. Redox Biol. 57, 102497 (2022).
Xiao, Q., McAtee, C. K. & Su, X. Phase separation in immune signalling. Nat. Rev. Immunol. 22, 188–199 (2022).
Hirose, T., Ninomiya, K., Nakagawa, S. & Yamazaki, T. A guide to membraneless organelles and their various roles in gene regulation. Nat. Rev. Mol. Cell Biol. 24, 288–304 (2023).
Mitrea, D. M., Mittasch, M., Gomes, B. F., Klein, I. A. & Murcko, M. A. Modulating biomolecular condensates: a novel approach to drug discovery. Nat. Rev. Drug Discov. 21, 841–862 (2022).
Snead, W. T. & Gladfelter, A. S. The control centers of biomolecular phase separation: how membrane surfaces, PTMs, and active processes regulate condensation. Mol. Cell 76, 295–305 (2019).
Roden, C. & Gladfelter, A. S. RNA contributions to the form and function of biomolecular condensates. Nat. Rev. Mol. Cell Biol. 22, 183–195 (2021).
Wiedner, H. J. & Giudice, J. It’s not just a phase: function and characteristics of RNA-binding proteins in phase separation. Nat. Struct. Mol. Biol. 28, 465–473 (2021).
Huang, X. et al. ROS regulated reversible protein phase separation synchronizes plant flowering. Nat. Chem. Biol. 17, 549–557 (2021).
Kato, M. et al. Redox state controls phase separation of the yeast ataxin-2 protein via reversible oxidation of its methionine-rich low-complexity domain. Cell 177, 711–721.e8 (2019). This article details the mechanism by which H2O2 regulates phase separation though redox modification of methionine.
Lin, Y. et al. Redox-mediated regulation of an evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain. Proc. Natl Acad. Sci. USA 117, 28727–28734 (2020).
Yang, Y. S. et al. Yeast ataxin-2 forms an intracellular condensate required for the inhibition of TORC1 signaling during respiratory growth. Cell 177, 697–710.e17 (2019).
Kageyama, S. et al. p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response. Nat. Commun. 12, 16 (2021).
Sánchez-Martín, P. et al. NBR1-mediated p62-liquid droplets enhance the Keap1-Nrf2 system. EMBO Rep. 21, e48902 (2020).
Yang, Y., Valionyte, E., Kelly, J. & Luo, S. Histone H3F3/H3.3 chaperone DAXX converts to modulate SQSTM1 phase condensation for NFE2L2 activation. Autophagy 16, 171–172 (2020).
Yang, Y. et al. Cytoplasmic DAXX drives SQSTM1/p62 phase condensation to activate Nrf2-mediated stress response. Nat. Commun. 10, 3759 (2019).
Tan, C. T. et al. MOAP-1-mediated dissociation of p62/SQSTM1 bodies releases Keap1 and suppresses Nrf2 signaling. EMBO Rep. 22, e50854 (2021).
Lu, Y. et al. Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease. Sci. Transl. Med. 12, eaba3613 (2020).
Chen, L. & Liu, B. Relationships between stress granules, oxidative stress, and neurodegenerative diseases. Oxid. Med. Cell. Longev. 2017, 1809592 (2017).
Arimoto-Matsuzaki, K., Saito, H. & Takekawa, M. TIA1 oxidation inhibits stress granule assembly and sensitizes cells to stress-induced apoptosis. Nat. Commun. 7, 10252 (2016).
Luo, Y., Na, Z. & Slavoff, S. A. P-bodies: composition, properties, and functions. Biochemistry 57, 2424–2431 (2018).
Alluri, R. K., Li, Z. & McCrae, K. R. Stress granule-mediated oxidized RNA decay in P-body: hypothetical role of ADAR1, Tudor-SN, and STAU1. Front. Mol. Biosci. 8, 672988 (2021).
Bailey, A. P. et al. Antioxidant role for lipid droplets in a stem cell niche of Drosophila. Cell 163, 340–353 (2015).
Islam, A. et al. FABP7 protects astrocytes against ROS toxicity via lipid droplet formation. Mol. Neurobiol. 56, 5763–5779 (2019).
Amen, T. & Kaganovich, D. Stress granules inhibit fatty acid oxidation by modulating mitochondrial permeability. Cell Rep. 35, 109237 (2021).
Marschallinger, J. et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194–208 (2020).
Jin, M. et al. Glycolytic enzymes coalesce in g bodies under hypoxic stress. Cell Rep. 20, 895–908 (2017).
Khan, S. U., Rayees, S., Sharma, P. & Malik, F. Targeting redox regulation and autophagy systems in cancer stem cells. Clin. Exp. Med. 23, 1405–1423 (2023).
Toledo, B., González-Titos, A., Hernandez-Camarero, P. & Perán, M. A brief review on chemoresistance; targeting cancer stem cells as an alternative approach. Int. J. Mol. Sci. 24, 4487 (2023).
Diehn, M. et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780–783 (2009).
Ye, X. Q. et al. Mitochondrial and energy metabolism-related properties as novel indicators of lung cancer stem cells. Int. J. Cancer 129, 820–831 (2011).
Shi, X., Zhang, Y., Zheng, J. & Pan, J. Reactive oxygen species in cancer stem cells. Antioxid. Redox Signal. 16, 1215–1228 (2012).
Sancho, P., Barneda, D. & Heeschen, C. Hallmarks of cancer stem cell metabolism. Br. J. Cancer 114, 1305–1312 (2016).
Ishimoto, T. et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc− and thereby promotes tumor growth. Cancer Cell 19, 387–400 (2011). This article presents important evidence for the key role of cystine uptake via xCT in cancer stem cell survival through maintaining low intracellular ROS.
Kim, H. M. et al. Increased CD13 expression reduces reactive oxygen species, promoting survival of liver cancer stem cells via an epithelial-mesenchymal transition-like phenomenon. Ann. Surg. Oncol. 19, S539–S548 (2012).
Nakashima, M., Watanabe, M., Nakano, K., Uchimaru, K. & Horie, R. Differentiation of Hodgkin lymphoma cells by reactive oxygen species and regulation by heme oxygenase-1 through HIF-1α. Cancer Sci. 112, 2542–2555 (2021).
Somasundaram, V. et al. Selective mode of action of plumbagin through BRCA1 deficient breast cancer stem cells. BMC Cancer 16, 336 (2016).
Luo, M. et al. Targeting breast cancer stem cell state equilibrium through modulation of redox signaling. Cell Metab. 28, 69–86.e6 (2018). This study shows a major role for ROS in regulating cellular plasticity and the transition between quiescent mesenchymal-like and proliferative epithelial-like cancer stem cells.
Hallis, S. P., Kim, J. M. & Kwak, M. K. Emerging role of NRF2 signaling in cancer stem cell phenotype. Mol. Cell 46, 153–164 (2023). This review describes NRF2-mediated redox regulation in cancer stem cells and its therapeutic implications.
Kamble, D., Mahajan, M., Dhat, R. & Sitasawad, S. Keap1-Nrf2 pathway regulates ALDH and contributes to radioresistance in breast cancer stem. Cells 10, 83 (2021).
Trachootham, D. et al. Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism. Blood 112, 1912–1922 (2008).
Xu, C. et al. Activation of glucocorticoid receptor inhibits the stem-like properties of bladder cancer via inactivating the β-catenin pathway. Front. Oncol. 10, 1332 (2020).
Ju, H. Q. et al. Redox regulation of stem-like cells though the CD44v-xCT axis in colorectal cancer: mechanisms and therapeutic implications. Theranostics 6, 1160–1175 (2016).
Xu, C. et al. Doxorubicin and erastin co-loaded hydroxyethyl starch-polycaprolactone nanoparticles for synergistic cancer therapy. J. Control. Release 356, 256–271 (2023).
Chen, B. et al. Fangchinoline inhibits non-small cell lung cancer metastasis by reversing epithelial-mesenchymal transition and suppressing the cytosolic ROS-related Akt-mTOR signaling pathway. Cancer Lett. 543, 215783 (2022).
He, T. et al. Brusatol: a potential sensitizing agent for cancer therapy from Brucea javanica. Biomed. Pharmacother. 158, 114134 (2023).
Glorieux, C., Enriquez, C., Gonzalez, C., Aguirre-Martinez, G. & Buc Calderon, P. The multifaceted roles of NRF2 in cancer: friend or foe? Antioxidants 13, 70 (2024).
Luo, L., Pervaiz, S. & Clement, M. V. A superoxide-driven redox state promotes geroconversion and resistance to senolysis in replication-stress associated senescence. Redox Biol. 64, 102757 (2023).
Hanggi, K. & Ruffell, B. Cell death, therapeutics, and the immune response in cancer. Trends Cancer 9, 381–396 (2023).
Rothlin, C. V., Hille, T. D. & Ghosh, S. Determining the effector response to cell death. Nat. Rev. Immunol. 21, 292–304 (2021).
Tang, D., Kang, R., Berghe, T. V., Vandenabeele, P. & Kroemer, G. The molecular machinery of regulated cell death. Cell Res. 29, 347–364 (2019).
Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).
Yan, B. et al. Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1. Mol. Cell 81, 355–369 (2021).
Ingold, I. et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell 172, 409–422.e21 (2018).
Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014).
Hangauer, M. J. et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551, 247–250 (2017).
Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688–692 (2019).
Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693–698 (2019).
Mishima, E. et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 608, 778–783 (2022).
Mao, C. et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 593, 586–590 (2021).
Soula, M. et al. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat. Chem. Biol. 16, 1351–1360 (2020).
Jiang, L. et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 57–62 (2015).
Liang, D. et al. Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones. Cell 186, 2748–2764.e22 (2023).
Wang, W. et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569, 270–274 (2019). This study showcases the role of CD8+ T cells in causing ferroptosis in cancer cells and how redox modulation using cyst(e)inase could further enhance anticancer activity.
Kim, R. et al. Ferroptosis of tumour neutrophils causes immune suppression in cancer. Nature 612, 338–346 (2022). In contrast to the work by Wang et al. (2019), this article shows that ferroptosis of immune cells causes a suppression of antitumour immunity.
Kapralov, A. A. et al. Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Nat. Chem. Biol. 16, 278–290 (2020).
Wang, Y. et al. Mitochondrial ROS promote macrophage pyroptosis by inducing GSDMD oxidation. J. Mol. Cell. Biol. 11, 1069–1082 (2019).
Weindel, C. G. et al. Mitochondrial ROS promotes susceptibility to infection via gasdermin D-mediated necroptosis. Cell 185, 3214–3231.e23 (2022).
Devant, P. et al. Gasdermin D pore-forming activity is redox-sensitive. Cell Rep. 42, 112008 (2023).
Evavold, C. L. et al. Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway. Cell 184, 4495–4511.e19 (2021).
Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015).
Tschopp, J. & Schroder, K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat. Rev. Immunol. 10, 210–215 (2010).
Liu, T., Zhang, L., Joo, D. & Sun, S. C. NF-κB signaling in inflammation. Signal Transduct. Target. Ther. 2, 17023 (2017).
Zhou, B. et al. Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis. Cell Res. 28, 1171–1185 (2018).
Rogers, C. et al. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat. Commun. 10, 1689 (2019).
Demarco, B. et al. Caspase-8–dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality. Sci. Adv. 6, eabc3465 (2020).
Zhang, J. Y. et al. The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8. Cell Res. 31, 980–997 (2021).
Lu, L. et al. Emerging mechanisms of pyroptosis and its therapeutic strategy in cancer. Cell Death Discov. 8, 338 (2022).
Wei, X. et al. Role of pyroptosis in inflammation and cancer. Cell. Mol. Immunol. 19, 971–992 (2022).
Wang, Y. et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547, 99–103 (2017).
Zhang, Z. et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature 579, 415–420 (2020).
Wang, Q. et al. A bioorthogonal system reveals antitumour immune function of pyroptosis. Nature 579, 421–426 (2020).
Obeng, E. Apoptosis (programmed cell death) and its signals - a review. Braz. J. Biol. 81, 1133–1143 (2021).
Carneiro, B. A. & El-Deiry, W. S. Targeting apoptosis in cancer therapy. Nat. Rev. Clin. Oncol. 17, 395–417 (2020).
Barbouti, A., Amorgianiotis, C., Kolettas, E., Kanavaros, P. & Galaris, D. Hydrogen peroxide inhibits caspase-dependent apoptosis by inactivating procaspase-9 in an iron-dependent manner. Free Radic. Biol. Med. 43, 1377–1387 (2007).
Chong, S. J. F. et al. Noncanonical cell fate regulation by Bcl-2 proteins. Trends Cell Biol. 30, 537–555 (2020).
Diepstraten, S. T. et al. The manipulation of apoptosis for cancer therapy using BH3-mimetic drugs. Nat. Rev. Cancer 22, 45–64 (2022).
Seehawer, M. et al. Necroptosis microenvironment directs lineage commitment in liver cancer. Nature 562, 69–75 (2018).
Zhang, T. et al. ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis. Nature 606, 594–602 (2022).
Zhang, Y. et al. RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome. Nat. Commun. 8, 14329 (2017).
Yan, J., Wan, P., Choksi, S. & Liu, Z. G. Necroptosis and tumor progression. Trends Cancer 8, 21–27 (2022).
Fulda, S. Alternative cell death pathways and cell metabolism. Int. J. Cell Biol. 2013, 463637 (2013).
Kang, P. et al. Oxeiptosis: a novel pathway of melanocytes death in response to oxidative stress in vitiligo. Cell Death Discov. 8, 70 (2022).
Holze, C. et al. Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway. Nat. Immunol. 19, 130–140 (2018).
Pallichankandy, S. et al. Targeting oxeiptosis-mediated tumor suppression: a novel approach to treat colorectal cancers by sanguinarine. Cell Death Discov. 9, 94 (2023).
Yipp, B. G. & Kubes, P. NETosis: how vital is it? Blood 122, 2784–2794 (2013).
Papayannopoulos, V. Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol. 18, 134–147 (2018).
Lood, C. et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, 146–153 (2016).
Cools-Lartigue, J. et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J. Clin. Investig. 123, 3446–3458 (2013).
Wen, F., Shen, A., Choi, A., Gerner, E. W. & Shi, J. Extracellular DNA in pancreatic cancer promotes cell invasion and metastasis. Cancer Res. 73, 4256–4266 (2013).
Alexandre, J., Hu, Y., Lu, W., Pelicano, H. & Huang, P. Novel action of paclitaxel against cancer cells: bystander effect mediated by reactive oxygen species. Cancer Res. 67, 3512–3517 (2007).
Luis, G. et al. Tumor resistance to ferroptosis driven by Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells and Fatty Acid Biding Protein-4 (FABP4) in tumor microenvironment promote tumor recurrence. Redox Biol. 43, 102006 (2021).
Rusz, M. et al. Morpho-metabotyping the oxidative stress response. Sci. Rep. 11, 15471 (2021).
Pecchillo Cimmino, T., Ammendola, R., Cattaneo, F. & Esposito, G. NOX dependent ROS generation and cell metabolism. Int. J. Mol. Sci. 24, 2086 (2023).
Kesharwani, P., Chadar, R., Sheikh, A., Rizg, W. Y. & Safhi, A. Y. CD44-targeted nanocarrier for cancer therapy. Front. Pharmacol. 12, 800481 (2022).
Pang, J. et al. A cyclodiaryliodonium NOX inhibitor for the treatment of pancreatic cancer via enzyme-activable targeted delivery by sulfated glycosaminoglycan derivatives. Adv. Healthc. Mater. 12, 2203011 (2023).
Zhu, L. et al. Inhibition of NADPH oxidase-ROS signal using hyaluronic acid nanoparticles for overcoming radioresistance in cancer therapy. ACS Nano 16, 18708–18728 (2022).
Jenkins, B. H., Buckingham, J. F., Hanley, C. J. & Thomas, G. J. Targeting cancer-associated fibroblasts: challenges, opportunities and future directions. Pharmacol. Ther. 240, 108231 (2022).
Ford, K. et al. NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumors. Cancer Res. 80, 1846–1860 (2020).
Trachootham, D. et al. Loss of p53 in stromal fibroblasts promotes epithelial cell invasion through redox-mediated ICAM1 signal. Free Radic. Biol. Med. 58, 1–13 (2013).
Zou, D. et al. Pan-cancer analysis of NOS3 identifies its expression and clinical relevance in gastric cancer. Front. Oncol. 11, 592761 (2021).
Huang, Z. et al. Suppressed mitochondrial respiration via NOX5-mediated redox imbalance contributes to the antitumor activity of anlotinib in oral squamous cell carcinoma. J. Genet. Genomics 48, 582–594 (2021).
Li, H. et al. Targeting mitochondrial IDH2 enhances antitumor activity of cisplatin in lung cancer via ROS-mediated mechanism. Biomedicines 11, 475 (2023).
Mapuskar, K. A. et al. Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: an exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients. Redox Biol. 60, 102599 (2023).
Sishc, B. J. et al. Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide. Sci. Transl. Med. 13, eabb3768 (2021).
Alexander, M. S. et al. Pharmacologic ascorbate reduces radiation-induced normal tissue toxicity and enhances tumor radiosensitization in pancreatic cancer. Cancer Res. 78, 6838–6851 (2018).
Furqan, M. et al. Pharmacological ascorbate improves the response to platinum-based chemotherapy in advanced stage non-small cell lung cancer. Redox Biol. 53, 102318 (2022).
Petronek, M. S. et al. Magnetic resonance imaging of iron metabolism with T2* mapping predicts an enhanced clinical response to pharmacological ascorbate in patients with GBM. Clin. Cancer Res. 30, 283–293 (2024). This article provides important clinical evidence for the effectiveness of vitamin C in enhancing the therapeutic activity of radiation and temozolomide via a ROS-mediated mechanism.
Eriksson, S. E., Ceder, S., Bykov, V. J. N. & Wiman, K. G. p53 as a hub in cellular redox regulation and therapeutic target in cancer. J. Mol. Cell. Biol. 11, 330–341 (2019).
Cheung, E. C. et al. Dynamic ROS control by TIGAR regulates the initiation and progression of pancreatic cancer. Cancer Cell 37, 168–182 (2020). This study reveals the different roles of ROS in different stages of cancer development and the underlying regulatory mechanisms.
Le Gal, K. et al. Antioxidants can increase melanoma metastasis in mice. Sci. Transl. Med. 7, 308 (2015). This article shows that antioxidants promote cancer metastasis in vivo, triggering further debates on the controversial roles of antioxidants in cancer treatment.
Wiel, C. et al. BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell 178, 330–345.e22 (2019).
Ahmed, S. M., Luo, L., Namani, A., Wang, X. J. & Tang, X. Nrf2 signaling pathway: pivotal roles in inflammation. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 585–597 (2017).
Ju, H. Q. et al. Mechanisms of overcoming intrinsic resistance to gemcitabine in pancreatic ductal adenocarcinoma through the redox modulation. Mol. Cancer Ther. 14, 788–798 (2015).
Lam-Ubol, A. et al. Sensory acceptable equivalent doses of β-phenylethyl isothiocyanate (PEITC) induce cell cycle arrest and retard the growth of p53 mutated oral cancer in vitro and in vivo. Food Funct. 9, 3640–3656 (2018).
Trachootham, D. et al. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by β-phenylethyl isothiocyanate. Cancer Cell 10, 241–252 (2006).
Wang, J. et al. Inhibition of cancer growth in vitro and in vivo by a novel ROS-modulating agent with ability to eliminate stem-like cancer cells. Cell Death Dis. 8, e2887 (2017).
Zhang, H. et al. Effective killing of Gleevec-resistant CML cells with T315I mutation by a natural compound PEITC through redox-mediated mechanism. Leukemia 22, 1191–1199 (2008).
Lam-Ubol, A. et al. Nutri-PEITC jelly significantly improves progression-free survival and quality of life in patients with advanced oral and oropharyngeal cancer: a blinded randomized placebo-controlled trial. Int. J. Mol. Sci. 24, 7824 (2023). This article provides clinical evidence for using natural redox-modulating compound PEITC to treat patients with cancer and achieving improvements in survival and life quality.
Tan, W. et al. GPX2 is a potential therapeutic target to induce cell apoptosis in lenvatinib against hepatocellular carcinoma. J. Adv. Res. 44, 173–183 (2023).
Gaschler, M. M. et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat. Chem. Biol. 14, 507–515 (2018).
Sun, Y. et al. Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells. Cell Death Dis. 12, 1028 (2021).
Augello, G. et al. New insights into the behavior of NHC-gold complexes in cancer cells. Pharmaceutics 15, 466 (2023).
Liu, X. et al. Tumor killing by a dietary curcumin mono-carbonyl analog that works as a selective ROS generator via TrxR inhibition. Eur. J. Med. Chem. 250, 115191 (2023).
Peng, S., Yu, S., Zhang, J. & Zhang, J. 6-Shogaol as a novel thioredoxin reductase inhibitor induces oxidative-stress-mediated apoptosis in HeLa cells. Int. J. Mol. Sci. 24, 4966 (2023).
Hou, Y. J. et al. Pathological mechanism of photodynamic therapy and photothermal therapy based on nanoparticles. Int. J. Nanomed. 15, 6827–6838 (2020).
Li, W. et al. Targeting photodynamic and photothermal therapy to the endoplasmic reticulum enhances immunogenic cancer cell death. Nat. Commun. 10, 3349 (2019).
Bondon, N. et al. Photosensitivity of different nanodiamond–PMO nanoparticles in two-photon-excited photodynamic therapy. Life 12, 2044 (2022).
Zhang, Y. et al. Chemotherapeutic drugs induce oxidative stress associated with DNA repair and metabolism modulation. Life Sci. 289, 120242 (2022).
Oberley, L. W. Anticancer therapy by overexpression of superoxide dismutase. Antioxid. Redox Signal. 3, 461–472 (2001).
Hadzic, T. et al. Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress. Free Radic. Biol. Med. 48, 1024–1033 (2010).
Chen, B. et al. A pyroptosis nanotuner for cancer therapy. Nat. Nanotechnol. 17, 788–798 (2022).
Fan, J. X. et al. Epigenetics-based tumor cells pyroptosis for enhancing the immunological effect of chemotherapeutic nanocarriers. Nano Lett. 19, 8049–8058 (2019).
Hu, J. et al. Local delivery of arsenic trioxide nanoparticles for hepatocellular carcinoma treatment. Signal Transduct. Target. Ther. 4, 28 (2019).
Kim, S. E. et al. Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nat. Nanotechnol. 11, 977–985 (2016).
Murphy, M. P. et al. Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo. Nat. Metab. 4, 651–662 (2022). This review article describes various methods and techniques for the detection of different reactive species and their potential pitfalls.
Owada, S. et al. Setanaxib as a potent hypoxia-specific therapeutic agent against liver cancer. Anticancer. Res. 40, 5071–5079 (2020).
Doroshow, J. H. et al. Effects of iodonium-class flavin dehydrogenase inhibitors on growth, reactive oxygen production, cell cycle progression, NADPH oxidase 1 levels, and gene expression in human colon cancer cells and xenografts. Free Radic. Biol. Med. 57, 162–175 (2013).
Chung, A. W. et al. A phase 1/2 clinical trial of the nitric oxide synthase inhibitor L-NMMA and taxane for treating chemoresistant triple-negative breast cancer. Sci. Transl. Med. 13, eabj5070 (2021).
Amatangelo, M. D. et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood 130, 732–741 (2017).
DiNardo, C. D. et al. Mutant isocitrate dehydrogenase 1 inhibitor ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia. J. Clin. Oncol. 39, 57–65 (2021).
Cluzeau, T. et al. Eprenetapopt plus azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a phase II study by the Groupe Francophone des Myélodysplasies (GFM). J. Clin. Oncol. 39, 1575–1583 (2021).
Sallman, D. A. et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J. Clin. Oncol. 39, 1584–1594 (2021).
Wu, X. et al. Regulation of GSK3β/Nrf2 signaling pathway modulated erastin-induced ferroptosis in breast cancer. Mol. Cell. Biochem. 473, 217–228 (2020).
Makker, V. et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N. Engl. J. Med. 386, 437–448 (2022).
Zhang, X. et al. Glutathione peroxidase 4 as a therapeutic target for anti-colorectal cancer drug-tolerant persister cells. Front. Oncol. 12, 913669 (2022).
Amato, R. J., Jac, J. & Hernandez-McClain, J. Motexafin gadolinium for the treatment of metastatic renal cell carcinoma: phase II study results. Clin. Genitourin. Cancer 6, 73–78 (2008).
Xiang, Y. et al. Brusatol enhances the chemotherapy efficacy of gemcitabine in pancreatic cancer via the Nrf2 signalling pathway. Oxid. Med. Cell. Longev. 2018, 2360427 (2018).
Chen, Z. et al. Brusatol suppresses the growth of intrahepatic cholangiocarcinoma by PI3K/Akt pathway. Phytomedicine 104, 154323 (2022).
Hanley, C. J. et al. Targeting the myofibroblastic cancer-associated fibroblast phenotype through inhibition of NOX4. J. Natl. Cancer Inst. 110, 109–120 (2018).
Sampson, N. et al. Inhibition of Nox4-dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal-mediated protumorigenic interactions. Int. J. Cancer 143, 383–395 (2018).
Xiao, Y. et al. Microenvironment-responsive prodrug-induced pyroptosis boosts cancer immunotherapy. Adv. Sci. 8, e2101840 (2021).
Tintelnot, J. et al. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature 615, 168–174 (2023).
Jaccard, A. et al. Reductive carboxylation epigenetically instructs T cell differentiation. Nature 621, 849–856 (2023).
Fan, H. et al. Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity. Nature 623, 1034–1043 (2023).
Acknowledgements
This work was supported in part by a grant from the Ministry of Science and Technology of the People’s Republic of China (2020YFA0803300). D.T. received support from Mahidol University Fundamental Fund: fiscal year 2023 by National Science Research and Innovation Fund (NSRF) of Thailand. We thank X. Xia of the Sun Yat-sen University Cancer Center for helpful discussion. The authors apologize for any papers and topics that could not be included in this article due to space limitations.
Author information
Authors and Affiliations
Contributions
All authors researched data for the article, contributed substantially to the discussion of its content, and wrote, reviewed and edited the manuscript before submission. C.G. and S.L. contributed equally to this work.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Drug Discovery thanks the anonymous reviewers for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Glorieux, C., Liu, S., Trachootham, D. et al. Targeting ROS in cancer: rationale and strategies. Nat Rev Drug Discov 23, 583–606 (2024). https://doi.org/10.1038/s41573-024-00979-4
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41573-024-00979-4
