Hostname: page-component-77f85d65b8-8wtlm Total loading time: 0 Render date: 2026-04-14T05:31:37.243Z Has data issue: false hasContentIssue false
  • English
  • Français

Manganese in health and disease

Published online by Cambridge University Press:  17 June 2025

Yingchen Wang ,
Jinyou Li ,
Jing Zhuang ,
Yinhang Wu ,
Jiang Liu  and
Shuwen Han
Yingchen Wang
Affiliation:
Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, People’s Republic of China Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang, People’s Republic of China Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, Huzhou, Zhejiang, People’s Republic of China
Jinyou Li
Affiliation:
Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, People’s Republic of China Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang, People’s Republic of China Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, Huzhou, Zhejiang, People’s Republic of China
Jing Zhuang
Affiliation:
Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, People’s Republic of China Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang, People’s Republic of China Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, Huzhou, Zhejiang, People’s Republic of China
Yinhang Wu
Affiliation:
Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, People’s Republic of China Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang, People’s Republic of China Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, Huzhou, Zhejiang, People’s Republic of China
Jiang Liu
Affiliation:
Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, People’s Republic of China Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang, People’s Republic of China Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, Huzhou, Zhejiang, People’s Republic of China
Shuwen Han*
Affiliation:
Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, People’s Republic of China Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang, People’s Republic of China Zhejiang-France United Laboratory of Integrated Traditional Chinese and Modern Medicine in Colorectal Cancer, Huzhou, Zhejiang, People’s Republic of China ASIR (Institute - Association of intelligent systems and robotics), 14B rue Henri Sainte Claire Deville, 92500, Rueil-Malmaison, France
*
Corresponding author: Shuwen Han; Email: shuwenhan985@163.com
Get access Rights & Permissions [Opens in a new window]

Abstract

Manganese (Mn) is a crucial trace element that actively participates in a diverse array of physiological processes. Mn is maintained at appropriate levels in the body by absorption and excretion by the body. Dysregulation of Mn homeostasis can lead to a variety of diseases, especially the accumulation of Mn in the brain, resulting in toxic side effects. We reviewed the metabolism and distribution of Mn at multiple levels, including organ, cellular and sub-cell levels. Mitochondria are the main sites of Mn metabolism and energy conversion in cells. Enhanced Mn superoxide dismutase activity reduces mitochondrial oxidative stress and inhibits cancer development. In addition, Mn enhances anti-cancer immune responses through the cGAS–STING pathway. We introduced various delivery vectors for Mn delivery to cancer sites for Mn supplementation and anti-cancer immunity. This review aims to provide new research perspectives for the application of Mn in the prevention and treatment of human diseases, especially by enhancing anti-cancer immune responses to inhibit cancer progression.

Keywords

Trace elementsManganeseMitochondriacGAS–STINGManganese nanomaterialsCancer

Information

Type
Review Article
Information
Nutrition Research Reviews , Volume 38 , Issue 2 , December 2025 , pp. 900 - 910
Check for updates
Copyright
© The Author(s), 2025. Published by Cambridge University Press on behalf of The Nutrition Society

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

Wang, H S, Lineweaver, C H, Ireland, T R. (2018) The elemental abundances (with uncertainties) of the most Earth-like planet. Icarus 299, 460–474.CrossRefGoogle Scholar
Wang, X, Wang, Q, Zhang, D, et al. (2024) Fumigation alters the manganese-oxidizing microbial communities to enhance soil manganese availability and increase tomato yield. Sci Total Environ 919, 170882.CrossRefGoogle ScholarPubMed
Zhuang, Y, Zhu, J, Shi, L, et al. (2022) Influence mechanisms of iron, aluminum and manganese oxides on the mineralization of organic matter in paddy soil. J Environ Manage 301, 113916.CrossRefGoogle ScholarPubMed
Parmalee, N L, Aschner, M. (2016) Manganese and aging. Neurotoxicology 56, 262–268.CrossRefGoogle ScholarPubMed
Chen, P, Bornhorst, J, Aschner, M. (2018) Manganese metabolism in humans. Front Biosci 23, 1655–1679.CrossRefGoogle ScholarPubMed
Kawahara, M, Kato-negishi, M, Tanaka, K I. (2023) Dietary trace elements and the pathogenesis of neurodegenerative diseases. Nutrients 15, 2067.CrossRefGoogle ScholarPubMed
Schmidt, S B, Jensen, P E, Husted, S. (2016) Manganese deficiency in plants: the impact on photosystem II. Trends Plant Sci 21, 622–632.CrossRefGoogle ScholarPubMed
Spears, J W. (2019) Boron, chromium, manganese, and nickel in agricultural animal production. Biol Trace Elem Res 188, 35–44.CrossRefGoogle ScholarPubMed
Tarnacka, B, Jopowicz, A, Maślińska, M. (2021) Copper, iron, and manganese toxicity in neuropsychiatric conditions. Int J Mol Sci 22, 7820.CrossRefGoogle ScholarPubMed
Viegas, M N, Salgado, M A, Aguiar, C, et al. (2021) Effect of dietary manganese and zinc levels on growth and bone status of Senegalese Sole (Solea senegalensis) post-larvae. Biol Trace Elem Res 199, 2012–2021.CrossRefGoogle ScholarPubMed
Xia, Y, Wang, C, Zhang, X, et al. (2023) Combined effects of lead and manganese on locomotor activity and microbiota in zebrafish. Ecotoxicol Environ Saf 263, 115260.CrossRefGoogle ScholarPubMed
Martins, A C JR., Ruella Oliveira, S, Barbosa, F JR., et al. (2021) Evaluating the risk of manganese-induced neurotoxicity of parenteral nutrition: review of the current literature. Expert Opin on Drug Metab & Toxicol 17, 581–593.CrossRefGoogle ScholarPubMed
Miah, M R, Ijomone, O M, Okoh, C O A, et al. (2020) The effects of manganese overexposure on brain health. Neurochem Int 135, 104688.CrossRefGoogle ScholarPubMed
Peres, T V, Schettinger, M R, Chen, P, et al. (2016) Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies. BMC Pharmacol Toxicol 17, 57.CrossRefGoogle ScholarPubMed
Zhou, B, Su, X, Su, D, et al. (2016) Dietary intake of manganese and the risk of the metabolic syndrome in a Chinese population. Br J Nutr 116, 853–863.CrossRefGoogle ScholarPubMed
Einhorn, V, Haase, H, Maares, M. (2024) Interaction and competition for intestinal absorption by zinc, iron, copper, and manganese at the intestinal mucus layer. J Trace Elem Med Biol 84, 127459.CrossRefGoogle ScholarPubMed
Myers, J E, Thompson, M L, Naik, I, et al. (2003) The utility of biological monitoring for manganese in ferroalloy smelter workers in South Africa. Neurotoxicology 24, 875–883.CrossRefGoogle ScholarPubMed
Wooten, A L, Aweda, T A, Lewis, B C, et al. (2017) Biodistribution and PET imaging of pharmacokinetics of manganese in mice using Manganese-52. PLoS One 12, e0174351.CrossRefGoogle ScholarPubMed
Palacios, C. (2006) The role of nutrients in bone health, from A to Z. Crit Rev Food Sci Nutr 46, 621–628.CrossRefGoogle ScholarPubMed
Strause, L G, Hegenauer, J, Saltman, P, et al. (1986) Effects of long-term dietary manganese and copper deficiency on rat skeleton. J Nutr 116, 135–141.CrossRefGoogle ScholarPubMed
Wang, X, Li, G J, Zheng, W. (2006) Upregulation of DMT1 expression in choroidal epithelia of the blood-CSF barrier following manganese exposure in vitro . Brain Res 1097, 1–10.CrossRefGoogle ScholarPubMed
Kwakye, G F, Paoliello, M M, Mukhopadhyay, S, et al. (2015) Manganese-induced Parkinsonism and Parkinson’s disease: shared and distinguishable features. Int J Environ Res Public Health 12, 7519–7540.CrossRefGoogle ScholarPubMed
Dobson, A W, Erikson, K M, Aschner, M. (2004) Manganese neurotoxicity. Ann N Y Acad Sci 1012, 115–128.CrossRefGoogle ScholarPubMed
Harischandra, D S, Ghaisas, S, Zenitsky, G, et al. (2019) Manganese-induced neurotoxicity: new insights into the triad of protein misfolding, mitochondrial impairment, and neuroinflammation. Front Neurosci 13, 654.CrossRefGoogle ScholarPubMed
Finkelstein, Y, Milatovic, D, Aschner, M. (2007) Modulation of cholinergic systems by manganese. Neurotoxicology 28, 1003–1014.CrossRefGoogle ScholarPubMed
Santos, D, Milatovic, D, Andrade, V, et al. (2012) The inhibitory effect of manganese on acetylcholinesterase activity enhances oxidative stress and neuroinflammation in the rat brain. Toxicology, 292, 90–98.CrossRefGoogle ScholarPubMed
Bouabid, S, Tinakoua, A, Lakhdar-Ghazal, N, et al. (2016) Manganese neurotoxicity: behavioral disorders associated with dysfunctions in the basal ganglia and neurochemical transmission. J Neurochem 136, 677–691.CrossRefGoogle ScholarPubMed
Stelling, M P, Soares, M A, Cardoso, S C, et al. (2021) Manganese systemic distribution is modulated in vivo during tumor progression and affects tumor cell migration and invasion in vitro . Sci Rep 11, 15833.CrossRefGoogle ScholarPubMed
Golara, A, Kozłowski, M, Guzik, P, et al. (2023) The role of selenium and manganese in the formation, diagnosis and treatment of cervical, endometrial and ovarian cancer. Int J Mol Sci 24, 10887.CrossRefGoogle ScholarPubMed
Sun, X, Zhang, Y, Li, J, et al. (2021) Amplifying STING activation by cyclic dinucleotide-manganese particles for local and systemic cancer metalloimmunotherapy. Nat Nanotechnol 16, 1260–1270.CrossRefGoogle ScholarPubMed
Yi, M, Niu, M, Zhang, J, et al. (2021) Combine and conquer: manganese synergizing anti-TGF-β/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers. J Hematol Oncol 14, 146.CrossRefGoogle ScholarPubMed
Zhang, K, Qi, C, Cai, K. (2023) Manganese-based tumor immunotherapy. Adv Mater 35, e2205409.CrossRefGoogle ScholarPubMed
Martins, A C, Krum, B N Queirós, L, et al. (2020) Manganese in the diet: bioaccessibility, adequate intake, and neurotoxicological effects. J Agric and Food Chem 68, 12893–12903.CrossRefGoogle ScholarPubMed
Teeguarden, J G, Gearhart, J, Clewell, H J, et al. (2007) Pharmacokinetic modeling of manganese. III. Physiological approaches accounting for background and tracer kinetics. J of Toxicol and Environ Health Part A 70, 1515–1526.CrossRefGoogle ScholarPubMed
Gunter, T E, Gerstner, B, Gunter, K K, et al. (2013) Manganese transport via the transferrin mechanism. Neurotoxicology 34, 118–127.CrossRefGoogle ScholarPubMed
Gruenheid, S, Canonne-Hergaux, F, Gauthier, S, et al. (1999) The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. J Exp Med 189, 831–841.CrossRefGoogle Scholar
Leavens, T L, Rao, D, Andersen, M E, et al. (2007) Evaluating transport of manganese from olfactory mucosa to striatum by pharmacokinetic modeling. Toxicol Sci : an Official J SocToxicol 97, 265–278.CrossRefGoogle ScholarPubMed
Bowler, R M, Beseler, C L, Gocheva, V V, et al. (2016) Environmental exposure to manganese in air: associations with tremor and motor function. The Sc Total Environ 541, 646–654.CrossRefGoogle ScholarPubMed
Lucchini, R G, Dorman, D C, Elder, A, et al. (2012) Neurological impacts from inhalation of pollutants and the nose-brain connection. Neurotoxicology 33, 838–841.CrossRefGoogle ScholarPubMed
Crossgrove, J, Zheng, W. (2004) Manganese toxicity upon overexposure. NMR in Biomedicine 17, 544–553.CrossRefGoogle ScholarPubMed
Murphy, V A, Wadhwani, K C, Smith, Q R, et al. (1991) Saturable transport of manganese(II) across the rat blood-brain barrier. J Neurochem 57, 948–954.CrossRefGoogle ScholarPubMed
Klaassen, C D. (1976) Biliary excretion of metals. Drug Metab Rev 5, 165–196.CrossRefGoogle ScholarPubMed
Omokhodion, F O, Howard, J M. (1994) Trace elements in the sweat of acclimatized persons. Clinica Chimica Acta; Int J Clin Chem 231, 23–28.CrossRefGoogle ScholarPubMed
Wang, C, Guan, Y, Lv, M, et al. (2018) Manganese increases the sensitivity of the cGAS-STING pathway for double-stranded DNA and is required for the host defense against DNA viruses. Immunity 48 675–687.CrossRefGoogle ScholarPubMed
Aschner, M, Erikson, K. (2017) Manganese. Adv Nutr 8, 520–521.CrossRefGoogle ScholarPubMed
Barceloux, D G. (1999) Manganese. J toxicol Clin toxicol 37, 293–307.CrossRefGoogle ScholarPubMed
Chakraborty, S, Aschner, M. (2012) Altered manganese homeostasis: implications for BLI-3-dependent dopaminergic neurodegeneration and SKN-1 protection in C. elegans . Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) 26, 183–187.CrossRefGoogle ScholarPubMed
Liu, K, Jing, M J, Liu, C, et al. (2019) Effect of trehalose on manganese-induced mitochondrial dysfunction and neuronal cell damage in mice. Basic Clin Pharmacol Toxicol 125, 536–547.CrossRefGoogle ScholarPubMed
Khan, K, Wasserman, G A, Liu, X, et al. (2012) Manganese exposure from drinking water and children’s academic achievement. Neurotoxicology, 33, 91–97.CrossRefGoogle ScholarPubMed
Oulhote, Y, Mergler, D, Barbeau, B, et al. (2014) Neurobehavioral function in school-age children exposed to manganese in drinking water. Environ Health Perspect 122, 1343–1350.CrossRefGoogle ScholarPubMed
Freeland-Graves, J H, Mousa, T Y, KIM S. (2016) International variability in diet and requirements of manganese: causes and consequences. J Trace Elem Med Biol 38, 24–32.CrossRefGoogle Scholar
Sender, R, Fuchs, S, Milo, R. (2016) Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 14, e1002533.CrossRefGoogle ScholarPubMed
Wu, Q, Mu, Q, Xia, Z, et al. (2021) Manganese homeostasis at the host-pathogen interface and in the host immune system. Semin Cell Dev Biol 115, 45–53.CrossRefGoogle ScholarPubMed
Zaharik, M L, Finlay, B B. (2004) Mn2+ and bacterial pathogenesis. Front Biosci 9, 1035–1042.CrossRefGoogle ScholarPubMed
Hood, M I, Skaar, E P. (2012) Nutritional immunity: transition metals at the pathogen-host interface. Nat Rev Microbiol 10, 525–537.CrossRefGoogle ScholarPubMed
Zackular, J P, Chazin, W J, Skaar, E P. (2015) Nutritional immunity: S100 proteins at the host–pathogen interface. J Biol Chem 290, 18991–18998.CrossRefGoogle ScholarPubMed
Domej, W, Krachler, M, Goessler, W, et al. (2000) Concentrations of copper, zinc, manganese, rubidium, and magnesium in thoracic empyemata and corresponding sera. Biol Trace Elem Res 78, 53–66.CrossRefGoogle ScholarPubMed
Sheldon, J R, Skaar, E P. (2019) Metals as phagocyte antimicrobial effectors. Curr Opin Immunol, 60, 1–9.CrossRefGoogle ScholarPubMed
Cellier, M F, Courville, P, Campion, C. (2007) Nramp1 phagocyte intracellular metal withdrawal defense. Microbes Infect 9, 1662–1670.CrossRefGoogle ScholarPubMed
Martínez, J L, Delgado-Iribarren, A, Baquero, F. (1990) Mechanisms of iron acquisition and bacterial virulence. FEMS Microbiol Rev 6, 45–56.CrossRefGoogle ScholarPubMed
Horsburgh, M J, Wharton, S J, Cox, A G, et al. (2002) MntR modulates expression of the PerR regulon and superoxide resistance in Staphylococcus aureus through control of manganese uptake. Mol Microbiol 44, 1269–1286.CrossRefGoogle ScholarPubMed
Marra, A, Lawson, S, Asundi, J S, et al. (2002) In vivo characterization of the PSA genes from Streptococcus pneumoniae in multiple models of infection. Microbiology (Reading ) 148, 1483–1491.CrossRefGoogle ScholarPubMed
Kehres, D G, Zaharik, M L, Finlay, B B, et al. (2000) The NRAMP proteins of Salmonella typhimurium and Escherichia coli are selective manganese transporters involved in the response to reactive oxygen. Mol Microbiol 36, 1085–1100.CrossRefGoogle ScholarPubMed
Kehres, D G, Janakiraman, A, Slauch, J M, et al. (2002) SitABCD is the alkaline Mn(2+) transporter of Salmonella enterica serovar Typhimurium. J Bacteriol 184, 3159–3166.CrossRefGoogle Scholar
Perry, R D, Craig, S K, Abney, J, et al. (2012) Manganese transporters Yfe and MntH are Fur-regulated and important for the virulence of Yersinia pestis. Microbiology (Reading ) 158, 804–815.CrossRefGoogle ScholarPubMed
Bearden, S W, Perry, R D. (1999) The Yfe system of Yersinia pestis transports iron and manganese and is required for full virulence of plague. Mol Microbiol 32, 403–414.CrossRefGoogle ScholarPubMed
Green, R T, Todd, J D, Johnston, A W. (2013) Manganese uptake in marine bacteria; the novel MntX transporter is widespread in Roseobacters, Vibrios, Alteromonadales and the SAR11 and SAR116 clades. Isme j 7, 581–591.CrossRefGoogle ScholarPubMed
Cellier, M F, Bergevin, I, Boyer, E, et al. (2001) Polyphyletic origins of bacterial Nramp transporters. Trends Genet 17, 365–370.CrossRefGoogle ScholarPubMed
Courville, P, Chaloupka, R, Cellier, M F. (2006) Recent progress in structure-function analyses of Nramp proton-dependent metal-ion transporters. Biochem Cell Biol 84, 960–978.CrossRefGoogle ScholarPubMed
Ouyang, Z, He, M, Oman, T, et al. (2009) A manganese transporter, BB0219 (BmtA), is required for virulence by the Lyme disease spirochete, Borrelia burgdorferi . Proc Natl Acad Sci U S A 106, 3449–3454.CrossRefGoogle ScholarPubMed
Kehl-Fie, T E, Zhang, Y, Moore, J L, et al. (2013) MntABC and MntH contribute to systemic Staphylococcus aureus infection by competing with calprotectin for nutrient manganese. Infect Immun 81, 3395–3405.CrossRefGoogle ScholarPubMed
Zeinert, R, Martinez, E, Schmitz, J, et al. (2018) Structure-function analysis of manganese exporter proteins across bacteria. J Biol Chem 293, 5715–5730.CrossRefGoogle ScholarPubMed
Grunenwald, C M, Choby, J E, Juttukonda, L J, et al. (2019) Manganese detoxification by MntE is critical for resistance to oxidative stress and virulence of Staphylococcus aureus . mBio 10, e02915-18.CrossRefGoogle ScholarPubMed
Wolfe, A L, Felock, P J, Hastings, J C, et al. (1996) The role of manganese in promoting multimerization and assembly of human immunodeficiency virus type 1 integrase as a catalytically active complex on immobilized long terminal repeat substrates. J Virol 70, 1424–1432.CrossRefGoogle ScholarPubMed
Vartanian, J P, Sala, M, Henry, M, et al. (1999) Manganese cations increase the mutation rate of human immunodeficiency virus type 1 ex vivo. J Gen Virol 80, 1983–1986.CrossRefGoogle ScholarPubMed
Villani, G, Tanguy Le Gac, N, Wasungu, L, et al. (2002) Effect of manganese on in vitro replication of damaged DNA catalyzed by the herpes simplex virus type-1 DNA polymerase. Nucleic Acids Res 30, 3323–3332.CrossRefGoogle ScholarPubMed
Wolff, N A, Garrick, M D, Zhao, L, et al. (2018) A role for divalent metal transporter (DMT1) in mitochondrial uptake of iron and manganese. Sci Rep 8, 211.CrossRefGoogle ScholarPubMed
Morello, M, Canini, A, Mattioli, P, et al. (2008) Sub-cellular localization of manganese in the basal ganglia of normal and manganese-treated rats an electron spectroscopy imaging and electron energy-loss spectroscopy study. Neurotoxicology 29, 60–72.CrossRefGoogle ScholarPubMed
Zhang, S, Zhou, Z, Fu, J. (2003) Effect of manganese chloride exposure on liver and brain mitochondria function in rats. Environ Res 93, 149–157.CrossRefGoogle ScholarPubMed
Ijomone, O M, Aluko, O M, Okoh, C O A, et al. (2019) Role for calcium signaling in manganese neurotoxicity. J Trace Elem Med Biol 56, 146–155.CrossRefGoogle ScholarPubMed
Werner, E, Gokhale, A, Ackert, M, et al. (2022) The mitochondrial RNA granule modulates manganese-dependent cell toxicity. Mol Biol Cell 33, ar108.CrossRefGoogle ScholarPubMed
Popow, J, Alleaume, A M, Curk, T, et al. (2015) FASTKD2 is an RNA-binding protein required for mitochondrial RNA processing and translation. Rna 21, 1873–1884.CrossRefGoogle Scholar
Antonicka, H, Shoubridge, E A. (2015) Mitochondrial RNA granules are centers for posttranscriptional rna processing and ribosome biogenesis. Cell Rep 10, 920–932.CrossRefGoogle ScholarPubMed
Antonicka, H, Lin, Z Y, Janer, A, et al. (2020) A high-density human mitochondrial proximity interaction network. Cell Metab 32, 479–497.CrossRefGoogle ScholarPubMed
Liu, Z Q, Liu, K, Liu, Z F, et al. (2021) Manganese-induced alpha-synuclein overexpression aggravates mitochondrial damage by repressing PINK1/Parkin-mediated mitophagy. Food Chem Toxicol 152, 112213.CrossRefGoogle ScholarPubMed
Suski, J M, Lebiedzinska, M, Bonora, M, et al. (2012) Relation between mitochondrial membrane potential and ROS formation. Methods Mol Biol 810, 183–205.CrossRefGoogle ScholarPubMed
Cannino, G, Ciscato, F, Masgras, I, et al. (2018) Metabolic plasticity of tumor cell mitochondria. Front Oncol 8, 333.CrossRefGoogle ScholarPubMed
Polyak, K, Li, Y, Zhu, H, et al. (1998) Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat Genet 20, 291–293.CrossRefGoogle ScholarPubMed
Penta, J S, Johnson, F M, Wachsman, J T, et al. (2001) Mitochondrial DNA in human malignancy. Mutat Res 488, 119–133.CrossRefGoogle ScholarPubMed
Hochhauser, D. (2000) Relevance of mitochondrial DNA in cancer. Lancet 356, 181–182.CrossRefGoogle ScholarPubMed
HA H C, Thiagalingam, A, Nelkin, B D, et al. (2000) Reactive oxygen species are critical for the growth and differentiation of medullary thyroid carcinoma cells. Clin Cancer Res 6, 3783–3787.Google Scholar
Sundaresan, M, Yu, Z X, Ferrans, V J, et al. (1996) Regulation of reactive-oxygen-species generation in fibroblasts by Rac1. Biochem J 318, 379–382.CrossRefGoogle ScholarPubMed
Nie, H, Chen, G, He, J, et al. (2016) Mitochondrial common deletion is elevated in blood of breast cancer patients mediated by oxidative stress. Mitochondrion 26, 104–112.CrossRefGoogle ScholarPubMed
Kamata, H, Hirata, H. (1999) Redox regulation of cellular signalling. Cell Signal 11, 1–14.CrossRefGoogle ScholarPubMed
Sundaresan, M, Yu, Z X, Ferrans, V J, et al. (1995) Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270, 296–299.CrossRefGoogle ScholarPubMed
Guyton, K Z, Liu, Y, Gorospe, M, et al. (1996) Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury. J Biol Chem 271, 4138–4142.CrossRefGoogle ScholarPubMed
Rao, G N. (1996) Hydrogen peroxide induces complex formation of SHC-Grb2-SOS with receptor tyrosine kinase and activates Ras and extracellular signal-regulated protein kinases group of mitogen-activated protein kinases. Oncogene 13, 713–719.Google ScholarPubMed
Ekoue, D N, He, C, Diamond, A M, et al. (2017) Manganese superoxide dismutase and glutathione peroxidase-1 contribute to the rise and fall of mitochondrial reactive oxygen species which drive oncogenesis. Biochim Biophys Acta Bioenerg 1858, 628–632.CrossRefGoogle Scholar
Zhang, Y, Zhang, H M, Shi, Y, et al. (2010) Loss of manganese superoxide dismutase leads to abnormal growth and signal transduction in mouse embryonic fibroblasts. Free Radic Biol Med 49, 1255–1262.CrossRefGoogle ScholarPubMed
Wang, S, Ma, M, Liang, Q, et al. (2022) Single-atom manganese anchored on carbon dots for promoting mitochondrial targeting and photodynamic effect in cancer treatment. ACS Applied Nano Materials 5, 6679–6690.CrossRefGoogle Scholar
Lv, M, Chen, M, Zhang, R, et al. (2020) Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy. Cell Res 30, 966–979.CrossRefGoogle ScholarPubMed
Yang, M, Li, J, Gu, P, et al. (2021) The application of nanoparticles in cancer immunotherapy: targeting tumor microenvironment. Bioact Mater 6, 1973–1987.Google ScholarPubMed
Han, Y, Liu, D, Li, L. (2020) PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res 10, 727–742.Google ScholarPubMed
Salmaninejad, A, Valilou, S F, Shabgah, A G, et al. (2019) PD-1/PD-L1 pathway: basic biology and role in cancer immunotherapy. J Cell Physiol 234, 16824–16837.CrossRefGoogle ScholarPubMed
Shen, X, Zhang, L, Li, J, et al. (2019) Recent findings in the regulation of programmed death Ligand 1 expression. Front Immunol 10, 1337.CrossRefGoogle ScholarPubMed
Buchbinder, E I, Desai, A. (2016) CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol 39, 98–106.CrossRefGoogle ScholarPubMed
Herbst, R S, Giaccone, G, De Marinis, F, et al. (2020) Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. N Engl J Med 383, 1328–1339.CrossRefGoogle ScholarPubMed
Motzer, R J, Penkov, K, Haanen, J, et al. (2019) Avelumab plus Axitinib versus Sunitinib for advanced Renal-Cell Carcinoma. N Engl J Med 380, 1103–1115.CrossRefGoogle ScholarPubMed
Salik, B, Smyth, M J, Nakamura, K. (2020) Targeting immune checkpoints in hematological malignancies. J Hematol Oncol 13, 111.CrossRefGoogle ScholarPubMed
Chen, R, Manochakian, R, James, L, et al. (2020) Emerging therapeutic agents for advanced non-small cell lung cancer. J Hematol Oncol 13, 58.CrossRefGoogle ScholarPubMed
Zhu, X D, Sun, H C. (2019) Emerging agents and regimens for hepatocellular carcinoma. J Hematol Oncol 12, 110.CrossRefGoogle ScholarPubMed
Robert, C, Schachter, J, Long, G V, et al. (2015) Pembrolizumab versus Ipilimumab in advanced Melanoma. N Engl J Med 372, 2521–2532.CrossRefGoogle ScholarPubMed
Tang, B, Yan, X, Sheng, X, et al. (2019) Safety and clinical activity with an anti-PD-1 antibody JS001 in advanced melanoma or urologic cancer patients. J Hematol Oncol 12, 7.CrossRefGoogle ScholarPubMed
Qiu, Z, Chen, Z, Zhang, C, et al. (2019) Achievements and futures of immune checkpoint inhibitors in non-small cell lung cancer. Exp Hematol Oncol 8, 19.CrossRefGoogle ScholarPubMed
Yi, M, Jiao, D, Xu, H, et al. (2018) Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol Cancer 17, 129.CrossRefGoogle ScholarPubMed
Niu, M, Yi, M, Li, N, et al. (2021) Predictive biomarkers of anti-PD-1/PD-L1 therapy in NSCLC [J]. Exp Hematol Oncol 10, 18.CrossRefGoogle ScholarPubMed
Ghaffari, A, Peterson, N, Khalaj, K, et al. (2018) STING agonist therapy in combination with PD-1 immune checkpoint blockade enhances response to carboplatin chemotherapy in high-grade serous ovarian cancer. Br J Cancer 119, 440–449.CrossRefGoogle ScholarPubMed
Pan, B S, Perera, S A, Piesvaux, J A, et al. (2020) An orally available non-nucleotide STING agonist with antitumor activity. Science 369, eaba6098.CrossRefGoogle ScholarPubMed
Li, C, Li, T, Niu, K, et al. (2022) Mild phototherapy mediated by manganese dioxide-loaded mesoporous polydopamine enhances immunotherapy against colorectal cancer. Biomater Sci 10, 3647–3656.CrossRefGoogle ScholarPubMed
Cheng, L, Zhang, P, Liu, Y, et al. (2023) Multifunctional hybrid exosomes enhanced cancer chemo-immunotherapy by activating the STING pathway. Biomaterials 301, 122259.CrossRefGoogle ScholarPubMed
Marcus, A, Mao, A J, Lensink-Vasan, M, et al. (2018) Tumor-derived cGAMP triggers a STING-mediated interferon response in non-tumor cells to activate the NK cell response. Immunity 49, 754–763.CrossRefGoogle ScholarPubMed
Wang, X, Liu, Y, Xue, C, et al. (2022) A protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses. Nat Commun 13, 5685.CrossRefGoogle ScholarPubMed
Hayes, C, Donohoe, C L, Davern, M, et al. (2021) The oncogenic and clinical implications of lactate induced immunosuppression in the tumour microenvironment. Cancer Lett 500, 75–86.CrossRefGoogle ScholarPubMed
Ippolito, L, Morandi, A, Giannoni, E, et al. (2019) Lactate: a metabolic driver in the tumour landscape. Trends Biochem Sci 44, 153–166.CrossRefGoogle ScholarPubMed
Lee, E S, Gao, Z, Bae, Y H. (2008) Recent progress in tumor pH targeting nanotechnology. J Control Release 132, 164–170.CrossRefGoogle ScholarPubMed
Zhang, J, Xu, M, Mu, Y, et al. (2019) Reasonably retard O(2) consumption through a photoactivity conversion nanocomposite for oxygenated photodynamic therapy. Biomaterials 218, 119312.CrossRefGoogle ScholarPubMed
Luo, S, Yang, Y, Chen, L, et al. (2024) Outer membrane vesicle-wrapped manganese nanoreactor for augmenting cancer metalloimmunotherapy through hypoxia attenuation and immune stimulation. Acta Biomater 181, 402–414.CrossRefGoogle ScholarPubMed
Ning, Z, Yang, L, Yan, X, et al. (2022) Effect and mechanism of the Lenvatinib@H-MnO(2)-FA drug delivery system in targeting intrahepatic cholangiocarcinoma. Curr Pharm Des 28, 743–750.CrossRefGoogle ScholarPubMed
Zhou, Z H, Liang, S Y, Zhao, T C, et al. (2021) Overcoming chemotherapy resistance using pH-sensitive hollow MnO(2) nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma. J Nanobiotechnology 19, 157.CrossRefGoogle ScholarPubMed
Zheng, X, Zhang, J, Wang, J, et al. (2015) Polydopamine coatings in confined nanopore space: toward improved retention and release of hydrophilic cargo. J Phys Chem C 119, 24512–24521.CrossRefGoogle Scholar
Liu, J, Guo, C, Li, C, et al. (2023) Redox/pH-responsive hollow manganese dioxide nanoparticles for thyroid cancer treatment. Front Chem 11, 1249472.CrossRefGoogle ScholarPubMed
Wang, B, Wang, T, Jiang, T, et al. (2024) Circulating immunotherapy strategy based on pyroptosis and STING pathway: Mn-loaded paclitaxel prodrug nanoplatform against tumor progression and metastasis. Biomaterials 306, 122472.CrossRefGoogle ScholarPubMed
Catania, G, Rodella, G, Vanvarenberg, K, et al. (2023) Combination of hyaluronic acid conjugates with immunogenic cell death inducer and CpG for glioblastoma local chemo-immunotherapy elicits an immune response and induces long-term survival. Biomaterials 294, 122006.CrossRefGoogle ScholarPubMed
Liang, X, Wang, D, Zhao, Y, et al. (2024) Tumor microenvironment-responsive manganese-based nano-modulator activate the cGAS-STING pathway to enhance innate immune system response. J Nanobiotechnology 22, 535.CrossRefGoogle ScholarPubMed
Luo, G, Li, X, Lin, J, et al. (2023) Multifunctional calcium-manganese nanomodulator provides antitumor treatment and improved immunotherapy via reprogramming of the tumor microenvironment. ACS Nano 17, 15449–15465.CrossRefGoogle ScholarPubMed
Zhu, H, Xu, C, Geng, Y, et al. (2025) Endoplasmic reticulum-targeted polymer-manganese nanocomplexes for tumor immunotherapy. ACS Nano 19, 4959–4972.CrossRefGoogle ScholarPubMed
Tuakashikila, Y M, Mata, H M, Kabamba, M M, et al. (2023) Reference intervals for Cd, Hg, Mn and Pb in the general children population (3-14 years) of Kinshasa, Democratic Republic of Congo (DRC) between June 2019 and June 2020. Arch Public Health 81, 40.CrossRefGoogle ScholarPubMed
Williams, M, Todd, G D, Roney, N, et al. (2012) Agency for Toxic Substances and Disease Registry (ATSDR) Toxicological Profiles [M]. Toxicological Profile for Manganese. Atlanta (GA); Agency for Toxic Substances and Disease Registry (US).Google ScholarPubMed
O’neal, S L, Zheng, W. (2015) Manganese toxicity upon overexposure: a decade in review. Curr Environ Health Rep 2, 315–328.CrossRefGoogle ScholarPubMed
Rahil-Khazen, R, Bolann, B J, Myking, A, et al. (2002) Multi-element analysis of trace element levels in human autopsy tissues by using inductively coupled atomic emission spectrometry technique (ICP-AES). J Trace Elem Med Biol 16, 15–25.CrossRefGoogle Scholar
Liu, Y, Byrne, P, Wang, H, et al. (2014) A compact DD neutron generator-based NAA system to quantify manganese (Mn) in bone in vivo . Physiol Meas 35, 1899–1911.CrossRefGoogle ScholarPubMed
Morton, J, Tan, E, Leese, E, et al. (2014) Determination of 61 elements in urine samples collected from a non-occupationally exposed UK adult population. Toxicol Lett 231, 179–193.CrossRefGoogle ScholarPubMed
Luk, E E, Culotta, V C. (2001) Manganese superoxide dismutase in Saccharomyces cerevisiae acquires its metal co-factor through a pathway involving the Nramp metal transporter, Smf2p. J Biol Chem 276, 47556–47562.CrossRefGoogle ScholarPubMed
Radin, J N, Zhu, J, Brazel, E B, et al. (2019) Synergy between nutritional immunity and independent host defenses contributes to the importance of the MntABC manganese transporter during Staphylococcus aureus infection. Infect Immun 87, e00642-18.CrossRefGoogle Scholar
Handke, L D, Gribenko, A V, Timofeyeva, Y, et al. (2018) MntC-dependent manganese transport is essential for Staphylococcus aureus oxidative stress resistance and virulence. mSphere 3, e00336-18.CrossRefGoogle ScholarPubMed
Ouyang, A, Gasner, K M, Neville, S L, et al. (2022) MntP and YiiP contribute to manganese efflux in Salmonella enterica Serovar Typhimurium under conditions of manganese overload and nitrosative stress. Microbiol Spectr 10, e0131621.CrossRefGoogle ScholarPubMed
Veyrier, F J, Boneca, I G, Cellier, M F, et al. (2011) A novel metal transporter mediating manganese export (MntX) regulates the Mn to Fe intracellular ratio and Neisseria meningitidis virulence. PLoS Pathog 7, e1002261.CrossRefGoogle Scholar