{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T03:32:31Z","timestamp":1793935951452,"version":"4.8.0"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T00:00:00Z","timestamp":1725926400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T00:00:00Z","timestamp":1725926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Immune checkpoint blockade (ICB) has emerged as a promising therapeutic option for hepatocellular carcinoma (HCC), but resistance to ICB occurs and patient responses vary. Here, we uncover protein arginine methyltransferase 3 (PRMT3) as a driver for immunotherapy resistance in HCC. We show that PRMT3 expression is induced by ICB-activated T cells via an interferon-gamma (IFN\u03b3)-STAT1 signaling pathway, and higher PRMT3 expression levels correlate with reduced numbers of tumor-infiltrating CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells and poorer response to ICB. Genetic depletion or pharmacological inhibition of PRMT3 elicits an influx of T cells into tumors and reduces tumor size in HCC mouse models. Mechanistically, PRMT3 methylates HSP60 at R446 to induce HSP60 oligomerization and maintain mitochondrial homeostasis. Targeting PRMT3-dependent HSP60 methylation disrupts mitochondrial integrity and increases mitochondrial DNA (mtDNA) leakage, which results in cGAS\/STING-mediated anti-tumor immunity. Lastly, blocking PRMT3 functions synergize with PD-1 blockade in HCC mouse models. Our study thus identifies PRMT3 as a potential biomarker and therapeutic target to overcome immunotherapy resistance in HCC.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-52170-3","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T15:02:33Z","timestamp":1725980553000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Targeting PRMT3 impairs methylation and oligomerization of HSP60 to boost anti-tumor immunity by activating cGAS\/STING signaling"],"prefix":"10.1038","volume":"15","author":[{"given":"Yunxing","family":"Shi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongfeng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoru","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinglan","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiong","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1373-1669","authenticated-orcid":false,"given":"Liang","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiliang","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2467-3683","authenticated-orcid":false,"given":"Yunfei","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8922-7249","authenticated-orcid":false,"given":"Guocan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9694-9522","authenticated-orcid":false,"given":"Binkui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,10]]},"reference":[{"key":"52170_CR1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3322\/caac.21763","volume":"73","author":"RL Siegel","year":"2023","unstructured":"Siegel, R. L., Miller, K. D., Wagle, N. S. & Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin. 73, 17\u201348 (2023).","journal-title":"CA Cancer J. Clin."},{"key":"52170_CR2","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41575-022-00704-9","volume":"20","author":"C Yang","year":"2023","unstructured":"Yang, C. et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 20, 203\u2013222 (2023).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"52170_CR3","doi-asserted-by":"publisher","first-page":"1894","DOI":"10.1056\/NEJMoa1915745","volume":"382","author":"RS Finn","year":"2020","unstructured":"Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894\u20131905 (2020).","journal-title":"N. Engl. J. Med."},{"key":"52170_CR4","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.jhep.2019.09.025","volume":"72","author":"AL Cheng","year":"2020","unstructured":"Cheng, A. L., Hsu, C., Chan, S. L., Choo, S. P. & Kudo, M. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J. Hepatol. 72, 307\u2013319 (2020).","journal-title":"J. Hepatol."},{"key":"52170_CR5","doi-asserted-by":"publisher","first-page":"5309","DOI":"10.1016\/j.cell.2021.09.020","volume":"184","author":"G Morad","year":"2021","unstructured":"Morad, G., Helmink, B. A., Sharma, P. & Wargo, J. A. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell 184, 5309\u20135337 (2021).","journal-title":"Cell"},{"key":"52170_CR6","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/j.ccell.2020.07.004","volume":"38","author":"M de Miguel","year":"2020","unstructured":"de Miguel, M. & Calvo, E. Clinical challenges of immune checkpoint inhibitors. Cancer Cell 38, 326\u2013333 (2020).","journal-title":"Cancer Cell"},{"key":"52170_CR7","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.immuni.2022.11.014","volume":"56","author":"RQ Wu","year":"2023","unstructured":"Wu, R. Q. et al. Immune checkpoint therapy-elicited sialylation of IgG antibodies impairs antitumorigenic type I interferon responses in hepatocellular carcinoma. Immunity 56, 180\u2013192.e111 (2023).","journal-title":"Immunity"},{"key":"52170_CR8","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/s41421-023-00529-z","volume":"9","author":"GQ Zhu","year":"2023","unstructured":"Zhu, G. Q. et al. CD36(+) cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor. Cell Discov. 9, 25 (2023).","journal-title":"Cell Discov."},{"key":"52170_CR9","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38443-3","volume":"14","author":"J Liu","year":"2023","unstructured":"Liu, J. et al. PRMT1 mediated methylation of cGAS suppresses anti-tumor immunity. Nat. Commun. 14, 2806 (2023).","journal-title":"Nat. Commun."},{"key":"52170_CR10","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1038\/s41417-022-00464-3","volume":"30","author":"H Wang","year":"2023","unstructured":"Wang, H., Yang, L., Liu, M. & Luo, J. Protein post-translational modifications in the regulation of cancer hallmarks. Cancer Gene Ther. 30, 529\u2013547 (2023).","journal-title":"Cancer Gene Ther."},{"key":"52170_CR11","doi-asserted-by":"publisher","unstructured":"Wang, Z. et al. PRMT5 reduces immunotherapy efficacy in triple-negative breast cancer by methylating KEAP1 and inhibiting ferroptosis. J. Immunother. Cancer 11 https:\/\/doi.org\/10.1136\/jitc-2023-006890 (2023).","DOI":"10.1136\/jitc-2023-006890"},{"key":"52170_CR12","doi-asserted-by":"publisher","first-page":"2158","DOI":"10.1158\/2159-8290.CD-21-0205","volume":"12","author":"V Lukinovi\u0107","year":"2022","unstructured":"Lukinovi\u0107, V. et al. SMYD3 impedes small cell lung cancer sensitivity to alkylation damage through RNF113A Methylation-phosphorylation cross-talk. Cancer Discov. 12, 2158\u20132179 (2022).","journal-title":"Cancer Discov."},{"key":"52170_CR13","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-37542-5","volume":"14","author":"Y Shi","year":"2023","unstructured":"Shi, Y. et al. PRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer. Nat. Commun. 14, 1932 (2023).","journal-title":"Nat. Commun."},{"key":"52170_CR14","doi-asserted-by":"publisher","first-page":"17990","DOI":"10.1073\/pnas.1901323116","volume":"116","author":"S AbuHammad","year":"2019","unstructured":"AbuHammad, S. et al. Regulation of PRMT5-MDM4 axis is critical in the response to CDK4\/6 inhibitors in melanoma. Proc. Natl. Acad. Sci. USA 116, 17990\u201318000 (2019).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"52170_CR15","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1016\/j.tcb.2020.06.003","volume":"30","author":"M St Paul","year":"2020","unstructured":"St Paul, M. & Ohashi, P. S. The roles of CD8(+) T cell subsets in antitumor immunity. Trends Cell Biol. 30, 695\u2013704 (2020).","journal-title":"Trends Cell Biol."},{"key":"52170_CR16","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/s41416-020-01048-4","volume":"124","author":"H Raskov","year":"2021","unstructured":"Raskov, H., Orhan, A., Christensen, J. P. & G\u00f6genur, I. Cytotoxic CD8(+) T cells in cancer and cancer immunotherapy. Br. J. Cancer 124, 359\u2013367 (2021).","journal-title":"Br. J. Cancer"},{"key":"52170_CR17","first-page":"A68","volume":"19","author":"K Tomczak","year":"2015","unstructured":"Tomczak, K., Czerwi\u0144ska, P. & Wiznerowicz, M. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp. Oncol. 19, A68\u2013A77 (2015).","journal-title":"Contemp. Oncol."},{"key":"52170_CR18","doi-asserted-by":"publisher","DOI":"10.1002\/advs.201902880","volume":"7","author":"YR Miao","year":"2020","unstructured":"Miao, Y. R. et al. ImmuCellAI: a unique method for comprehensive T-cell subsets abundance prediction and its application in cancer immunotherapy. Adv. Sci. 7, 1902880 (2020).","journal-title":"Adv. Sci."},{"key":"52170_CR19","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nmeth.3337","volume":"12","author":"AM Newman","year":"2015","unstructured":"Newman, A. M. et al. Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods 12, 453\u2013457 (2015).","journal-title":"Nat. Methods"},{"key":"52170_CR20","doi-asserted-by":"publisher","first-page":"1550","DOI":"10.1038\/s41591-018-0136-1","volume":"24","author":"P Jiang","year":"2018","unstructured":"Jiang, P. et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat. Med. 24, 1550\u20131558 (2018).","journal-title":"Nat. Med."},{"key":"52170_CR21","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.ejca.2016.03.082","volume":"62","author":"LH Schwartz","year":"2016","unstructured":"Schwartz, L. H. et al. RECIST 1.1\u2014standardisation and disease-specific adaptations: perspectives from the RECIST Working Group. Eur. J. Cancer 62, 138\u2013145 (2016).","journal-title":"Eur. J. Cancer"},{"key":"52170_CR22","doi-asserted-by":"publisher","first-page":"1916","DOI":"10.1038\/s41591-019-0654-5","volume":"25","author":"D Liu","year":"2019","unstructured":"Liu, D. et al. Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma. Nat. Med. 25, 1916\u20131927 (2019).","journal-title":"Nat. Med."},{"key":"52170_CR23","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1016\/j.cell.2017.09.028","volume":"171","author":"N Riaz","year":"2017","unstructured":"Riaz, N. et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171, 934\u2013949.e916 (2017).","journal-title":"Cell"},{"key":"52170_CR24","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/j.ccell.2022.12.008","volume":"41","author":"G Li","year":"2023","unstructured":"Li, G. et al. Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy. Cancer Cell 41, 304\u2013322.e307 (2023).","journal-title":"Cancer Cell"},{"key":"52170_CR25","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1038\/s41586-021-03741-7","volume":"595","author":"H Jin","year":"2021","unstructured":"Jin, H. et al. EGFR activation limits the response of liver cancer to lenvatinib. Nature 595, 730\u2013734 (2021).","journal-title":"Nature"},{"key":"52170_CR26","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.ccell.2022.02.003","volume":"40","author":"P Liao","year":"2022","unstructured":"Liao, P. et al. CD8(+) T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell 40, 365\u2013378.e366 (2022).","journal-title":"Cancer Cell"},{"key":"52170_CR27","doi-asserted-by":"publisher","first-page":"9241","DOI":"10.1074\/jbc.270.16.9241","volume":"270","author":"GF Seelig","year":"1995","unstructured":"Seelig, G. F., Prosise, W. W., Hawkins, J. C. & Senior, M. M. Development of a receptor peptide antagonist to human gamma-interferon and characterization of its ligand-bound conformation using transferred nuclear Overhauser effect spectroscopy. J. Biol. Chem. 270, 9241\u20139249 (1995).","journal-title":"J. Biol. Chem."},{"key":"52170_CR28","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.neulet.2013.02.051","volume":"542","author":"MD King","year":"2013","unstructured":"King, M. D., Alleyne, C. H. Jr. & Dhandapani, K. M. TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice. Neurosci. Lett. 542, 92\u201396 (2013).","journal-title":"Neurosci. Lett."},{"key":"52170_CR29","doi-asserted-by":"crossref","unstructured":"ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57\u201374 (2012).","DOI":"10.1038\/nature11247"},{"key":"52170_CR30","doi-asserted-by":"publisher","first-page":"D165","DOI":"10.1093\/nar\/gkab1113","volume":"50","author":"JA Castro-Mondragon","year":"2022","unstructured":"Castro-Mondragon, J. A. et al. JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 50, D165\u2013d173 (2022).","journal-title":"Nucleic Acids Res."},{"key":"52170_CR31","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1093\/bioinformatics\/btr064","volume":"27","author":"CE Grant","year":"2011","unstructured":"Grant, C. E., Bailey, T. L. & Noble, W. S. FIMO: scanning for occurrences of a given motif. Bioinformatics 27, 1017\u20131018 (2011).","journal-title":"Bioinformatics"},{"key":"52170_CR32","doi-asserted-by":"publisher","unstructured":"Kumar, R. et al. A mitochondrial unfolded protein response inhibitor suppresses prostate cancer growth in mice via HSP60. J. Clin. Invest. 132 https:\/\/doi.org\/10.1172\/jci149906 (2022).","DOI":"10.1172\/jci149906"},{"key":"52170_CR33","doi-asserted-by":"publisher","first-page":"D529","DOI":"10.1093\/nar\/gky1079","volume":"47","author":"R Oughtred","year":"2019","unstructured":"Oughtred, R. et al. The BioGRID interaction database: 2019 update. Nucleic Acids Res. 47, D529\u2013d541 (2019).","journal-title":"Nucleic Acids Res."},{"key":"52170_CR34","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31809-z","volume":"13","author":"PC Havugimana","year":"2022","unstructured":"Havugimana, P. C. et al. Scalable multiplex co-fractionation\/mass spectrometry platform for accelerated protein interactome discovery. Nat. Commun. 13, 4043 (2022).","journal-title":"Nat. Commun."},{"key":"52170_CR35","doi-asserted-by":"crossref","unstructured":"Gomez, C. R. In Heat Shock Protein 60 in Human Diseases and Disorders (eds Asea, A. A. A. & Kaur, P.) 117\u2013134 (Springer International Publishing, 2019).","DOI":"10.1007\/978-3-030-23154-5_9"},{"key":"52170_CR36","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.cell.2019.08.052","volume":"179","author":"Q Gao","year":"2019","unstructured":"Gao, Q. et al. Integrated proteogenomic characterization of HBV-related hepatocellular carcinoma. Cell 179, 561\u2013577.e522 (2019).","journal-title":"Cell"},{"key":"52170_CR37","doi-asserted-by":"publisher","first-page":"e108","DOI":"10.1158\/0008-5472.CAN-17-0307","volume":"77","author":"T Li","year":"2017","unstructured":"Li, T. et al. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 77, e108\u2013e110 (2017).","journal-title":"Cancer Res."},{"key":"52170_CR38","doi-asserted-by":"publisher","first-page":"95","DOI":"10.3389\/fmolb.2020.00095","volume":"7","author":"C Caruso Bavisotto","year":"2020","unstructured":"Caruso Bavisotto, C. et al. Hsp60 post-translational modifications: functional and pathological consequences. Front. Mol. Biosci. 7, 95 (2020).","journal-title":"Front. Mol. Biosci."},{"key":"52170_CR39","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1186\/s13046-021-01904-y","volume":"40","author":"C Wang","year":"2021","unstructured":"Wang, C. et al. Elafin promotes tumour metastasis and attenuates the anti-metastatic effects of erlotinib via binding to EGFR in hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 40, 113 (2021).","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"52170_CR40","doi-asserted-by":"publisher","unstructured":"Caruso Bavisotto, C. et al. Oligomeric state and holding activity of Hsp60. Int. J. Mol. Sci. 24 https:\/\/doi.org\/10.3390\/ijms24097847 (2023).","DOI":"10.3390\/ijms24097847"},{"key":"52170_CR41","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1016\/j.immuni.2022.04.006","volume":"55","author":"SF Erttmann","year":"2022","unstructured":"Erttmann, S. F. et al. The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis. Immunity 55, 847\u2013861.e810 (2022).","journal-title":"Immunity"},{"key":"52170_CR42","doi-asserted-by":"publisher","first-page":"28198","DOI":"10.1074\/jbc.M109.031997","volume":"284","author":"A Parnas","year":"2009","unstructured":"Parnas, A. et al. The MitCHAP-60 disease is due to entropic destabilization of the human mitochondrial Hsp60 oligomer. J. Biol. Chem. 284, 28198\u201328203 (2009).","journal-title":"J. Biol. Chem."},{"key":"52170_CR43","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.686","volume":"12","author":"Y Lei","year":"2022","unstructured":"Lei, Y. et al. Protein arginine methyltransferase 3 promotes glycolysis and hepatocellular carcinoma growth by enhancing arginine methylation of lactate dehydrogenase A. Clin. Transl. Med. 12, e686 (2022).","journal-title":"Clin. Transl. Med."},{"key":"52170_CR44","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1038\/s41419-021-04352-w","volume":"12","author":"X Zhang","year":"2021","unstructured":"Zhang, X. et al. PRMT3 promotes tumorigenesis by methylating and stabilizing HIF1\u03b1 in colorectal cancer. Cell Death Dis. 12, 1066 (2021).","journal-title":"Cell Death Dis."},{"key":"52170_CR45","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1038\/s41419-022-05389-1","volume":"13","author":"Y Liao","year":"2022","unstructured":"Liao, Y. et al. PRMT3 drives glioblastoma progression by enhancing HIF1A and glycolytic metabolism. Cell Death Dis. 13, 943 (2022).","journal-title":"Cell Death Dis."},{"key":"52170_CR46","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/s13046-023-02614-3","volume":"42","author":"J Lv","year":"2023","unstructured":"Lv, J. et al. HNRNPL induced circFAM13B increased bladder cancer immunotherapy sensitivity via inhibiting glycolysis through IGF2BP1\/PKM2 pathway. J. Exp. Clin. Cancer Res. 42, 41 (2023).","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"52170_CR47","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1158\/0008-5472.CAN-21-1323","volume":"82","author":"Z Ni","year":"2022","unstructured":"Ni, Z. et al. JNK signaling promotes bladder cancer immune escape by regulating METTL3-mediated m6A modification of PD-L1 mRNA. Cancer Res. 82, 1789\u20131802 (2022).","journal-title":"Cancer Res."},{"key":"52170_CR48","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1053\/j.gastro.2023.04.032","volume":"165","author":"J Zhai","year":"2023","unstructured":"Zhai, J. et al. ALKBH5 drives immune suppression via targeting AXIN2 to promote colorectal cancer and is a target for boosting immunotherapy. Gastroenterology 165, 445\u2013462 (2023).","journal-title":"Gastroenterology"},{"key":"52170_CR49","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1038\/nature14404","volume":"523","author":"S Spranger","year":"2015","unstructured":"Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic \u03b2-catenin signalling prevents anti-tumour immunity. Nature 523, 231\u2013235 (2015).","journal-title":"Nature"},{"key":"52170_CR50","doi-asserted-by":"publisher","first-page":"e2214956120","DOI":"10.1073\/pnas.2214956120","volume":"120","author":"J Zhu","year":"2023","unstructured":"Zhu, J. et al. Asymmetric arginine dimethylation of cytosolic RNA and DNA sensors by PRMT3 attenuates antiviral innate immunity. Proc. Natl. Acad. Sci. USA 120, e2214956120 (2023).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"52170_CR51","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32283-3","volume":"13","author":"Y Lu","year":"2022","unstructured":"Lu, Y. et al. A single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma. Nat. Commun. 13, 4594 (2022).","journal-title":"Nat. Commun."},{"key":"52170_CR52","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.cell.2020.08.040","volume":"183","author":"A Sharma","year":"2020","unstructured":"Sharma, A. et al. Onco-fetal reprogramming of endothelial cells drives immunosuppressive macrophages in hepatocellular carcinoma. Cell 183, 377\u2013394.e321 (2020).","journal-title":"Cell"},{"key":"52170_CR53","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.abb.2010.09.024","volume":"505","author":"Y Gu","year":"2011","unstructured":"Gu, Y., Ande, S. R. & Mishra, S. Altered O-GlcNAc modification and phosphorylation of mitochondrial proteins in myoblast cells exposed to high glucose. Arch. Biochem. Biophys. 505, 98\u2013104 (2011).","journal-title":"Arch. Biochem. Biophys."},{"key":"52170_CR54","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1089\/ars.2012.4606","volume":"20","author":"MM Rahaman","year":"2014","unstructured":"Rahaman, M. M. et al. S-guanylation proteomics for redox-based mitochondrial signaling. Antioxid. Redox Signal. 20, 295\u2013307 (2014).","journal-title":"Antioxid. Redox Signal."},{"key":"52170_CR55","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1016\/j.freeradbiomed.2009.12.019","volume":"48","author":"HB Suliman","year":"2010","unstructured":"Suliman, H. B. et al. Nitric oxide synthase-2 regulates mitochondrial Hsp60 chaperone function during bacterial peritonitis in mice. Free Radic. Biol. Med. 48, 736\u2013746 (2010).","journal-title":"Free Radic. Biol. Med."},{"key":"52170_CR56","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7819-11-260","volume":"11","author":"Z Jiang","year":"2013","unstructured":"Jiang, Z. et al. Investigating citrullinated proteins in tumour cell lines. World J. Surg. Oncol. 11, 260 (2013).","journal-title":"World J. Surg. Oncol."},{"key":"52170_CR57","doi-asserted-by":"publisher","first-page":"3401","DOI":"10.1002\/pmic.200400971","volume":"4","author":"SK Suh","year":"2004","unstructured":"Suh, S. K. et al. Identification of oxidized mitochondrial proteins in alcohol-exposed human hepatoma cells and mouse liver. Proteomics 4, 3401\u20133412 (2004).","journal-title":"Proteomics"},{"key":"52170_CR58","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1016\/j.jnutbio.2013.12.008","volume":"25","author":"Y Li","year":"2014","unstructured":"Li, Y., Malkaram, S. A., Zhou, J. & Zempleni, J. Lysine biotinylation and methionine oxidation in the heat shock protein HSP60 synergize in the elimination of reactive oxygen species in human cell cultures. J. Nutr. Biochem. 25, 475\u2013482 (2014).","journal-title":"J. Nutr. Biochem."},{"key":"52170_CR59","doi-asserted-by":"publisher","first-page":"3823","DOI":"10.1002\/elps.201000361","volume":"31","author":"Y Lim","year":"2010","unstructured":"Lim, Y., Hong, E., Kwon, D. & Lee, E. Proteomic identification and comparative analysis of asymmetrically arginine-methylated proteins in immortalized, young and senescent cells. Electrophoresis 31, 3823\u20133833 (2010).","journal-title":"Electrophoresis"},{"key":"52170_CR60","doi-asserted-by":"publisher","first-page":"1246","DOI":"10.3892\/etm.2021.10681","volume":"22","author":"N Wang","year":"2021","unstructured":"Wang, N. et al. Suppressing TRAP1 sensitizes glioblastoma multiforme cells to temozolomide. Exp. Ther. Med. 22, 1246 (2021).","journal-title":"Exp. Ther. Med."},{"key":"52170_CR61","doi-asserted-by":"publisher","first-page":"168","DOI":"10.3109\/10715762.2013.858147","volume":"48","author":"R Magnoni","year":"2014","unstructured":"Magnoni, R. et al. The Hsp60 folding machinery is crucial for manganese superoxide dismutase folding and function. Free Radic. Res. 48, 168\u2013179 (2014).","journal-title":"Free Radic. Res."},{"key":"52170_CR62","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1016\/j.immuni.2020.03.004","volume":"52","author":"E Mohamed","year":"2020","unstructured":"Mohamed, E. et al. The unfolded protein response mediator PERK governs myeloid cell-driven immunosuppression in tumors through inhibition of STING signaling. Immunity 52, 668\u2013682.e667 (2020).","journal-title":"Immunity"},{"key":"52170_CR63","doi-asserted-by":"publisher","unstructured":"Hsu, M. C. et al. Protein arginine methyltransferase 3 enhances chemoresistance in pancreatic cancer by methylating hnRNPA1 to increase ABCG2 expression. Cancers 11 https:\/\/doi.org\/10.3390\/cancers11010008 (2018).","DOI":"10.3390\/cancers11010008"},{"key":"52170_CR64","doi-asserted-by":"publisher","first-page":"e2303812","DOI":"10.1002\/advs.202303812","volume":"10","author":"Y Wang","year":"2023","unstructured":"Wang, Y. et al. PRMT3-mediated arginine methylation of METTL14 promotes malignant progression and treatment resistance in endometrial carcinoma. Adv. Sci. 10, e2303812 (2023).","journal-title":"Adv. Sci."},{"key":"52170_CR65","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1007\/s10495-021-01663-3","volume":"26","author":"A Murao","year":"2021","unstructured":"Murao, A., Aziz, M., Wang, H., Brenner, M. & Wang, P. Release mechanisms of major DAMPs. Apoptosis Int. J. Program. Cell Death 26, 152\u2013162 (2021).","journal-title":"Apoptosis Int. J. Program. Cell Death"},{"key":"52170_CR66","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1038\/s41568-022-00466-1","volume":"22","author":"CM Laumont","year":"2022","unstructured":"Laumont, C. M., Banville, A. C., Gilardi, M., Hollern, D. P. & Nelson, B. H. Tumour-infiltrating B cells: immunological mechanisms, clinical impact and therapeutic opportunities. Nat. Rev. Cancer 22, 414\u2013430 (2022).","journal-title":"Nat. Rev. Cancer"},{"key":"52170_CR67","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1038\/s41577-019-0127-6","volume":"19","author":"DG DeNardo","year":"2019","unstructured":"DeNardo, D. G. & Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol. 19, 369\u2013382 (2019).","journal-title":"Nat. Rev. Immunol."},{"key":"52170_CR68","doi-asserted-by":"publisher","unstructured":"Sung, P. S. et al. Intrahepatic inflammatory IgA(+)PD-L1(high) monocytes in hepatocellular carcinoma development and immunotherapy. J. Immunother. Cancer 10 https:\/\/doi.org\/10.1136\/jitc-2021-003618 (2022).","DOI":"10.1136\/jitc-2021-003618"},{"key":"52170_CR69","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.ejca.2016.03.081","volume":"62","author":"LH Schwartz","year":"2016","unstructured":"Schwartz, L. H. et al. RECIST 1.1-update and clarification: from the RECIST committee. Eur. J. Cancer 62, 132\u2013137 (2016).","journal-title":"Eur. J. Cancer"},{"key":"52170_CR70","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.jhep.2019.09.026","volume":"72","author":"JM Llovet","year":"2020","unstructured":"Llovet, J. M. & Lencioni, R. mRECIST for HCC: performance and novel refinements. J. Hepatol. 72, 288\u2013306 (2020).","journal-title":"J. Hepatol."},{"key":"52170_CR71","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","volume":"16","author":"I Korsunsky","year":"2019","unstructured":"Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289\u20131296 (2019).","journal-title":"Nat. Methods"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-52170-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-52170-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-52170-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T16:20:24Z","timestamp":1725985224000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-52170-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,10]]},"references-count":71,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["52170"],"URL":"https:\/\/doi.org\/10.1038\/s41467-024-52170-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.05.23.595475","asserted-by":"object"}]},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,10]]},"assertion":[{"value":"17 November 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 August 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 September 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7930"}}