{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T21:08:49Z","timestamp":1789160929919,"version":"build-2803163510"},"reference-count":41,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Melanoma, a highly malignant tumor originating from melanocytes, has seen a significant increase in global incidence, particularly among the elderly. Anti\u2010PD\u20101 monoclonal antibodies, which activate the immune system to attack cancer cells by blocking the PD\u20101\/PD\u2010L1 signaling pathway, have improved survival rates but face challenges such as innate resistance. This study enrolls 37 melanoma patients and 7 benign nevus patients, with tissue samples collected for analysis. RT\u2010qPCR and Western blot are used to quantify the expression of the target protein. Flow cytometry is utilized to analyze immune subsets in tumors. Glucose uptake, lactate production, and ATP level are assessed by commercial kits. Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) are measured using a Seahorse XF Analyzer. RNA Bisulfite Sequencing is performed to quantify pyruvate kinase M2 (PKM2) m7G methylation level, MeRIP\u2010qPCR is conducted to validate the m7G methylation level of PKM2, and RIP assay is conducted to confirm POU4F1\u2010METTL1 interaction. The results show that POU Class 4 Homeobox 1 (POU4F1) is upregulated in melanoma tissues compared to benign nevi. Anti\u2010PD\u20101 treatment effectively reduces POU4F1 expression in sensitive B16\u2010F10\u2010M tumors and has no significant effect on resistant B16\u2010F10\u2010R tumors. POU4F1 overexpression induces profound metabolic alterations, including increased lactate production, glucose uptake, and ECAR, while suppressing OCR in B16\u2010F10\u2010M cells. POU4F1 overexpression also reduces the infiltration of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, M1\u2010macrophages, and NK cells, while increasing Treg and M2\u2010macrophage populations in B16\u2010F10\u2010M cells. Importantly, 3\u2010Bromopyruvate (a glycolysis inhibitor) reverses these effects. Mechanistically, POU4F1 upregulates METTL1 expression and increases m7G methylation of PKM2 mRNA. Besides, there is an interaction between POU4F1 and METTL1. METTL1 is also overexpressed in melanoma tissues compared to benign nevi. In conclusion, POU4F1 drives anti\u2010PD\u20101 resistance in melanoma by enhancing glycolysis via METTL1\u2010mediated m7G methylation of PKM2. Targeting the POU4F1\u2010METTL1\u2010PKM2 axis may improve melanoma immunotherapy outcomes.\n                  <\/jats:p>","DOI":"10.1002\/mc.70049","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T13:44:54Z","timestamp":1759239894000},"page":"2063-2074","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["POU4F1 Promotes the Primary Resistance of Melanoma to Anti\u2010PD\u20101 Therapy by Regulating Glycolysis Through METTL1\u2010Mediated m7G Methylation of PKM2"],"prefix":"10.1002","volume":"64","author":[{"given":"Lin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Dermatology, Tangdu Hospital Fourth Military Medical University Xi\u2032an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaokang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Tangdu Hospital Fourth Military Medical University Xi\u2032an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhong","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Tangdu Hospital Fourth Military Medical University Xi\u2032an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Tangdu Hospital Fourth Military Medical University Xi\u2032an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Tangdu Hospital Fourth Military Medical University Xi\u2032an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5603-4289","authenticated-orcid":false,"given":"Ling","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Tangdu Hospital Fourth Military Medical University Xi\u2032an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"issue":"8","key":"e_1_2_11_2_1","article-title":"A Unique Case of High\u2010Grade Dedifferentiated Melanoma Without a Known Primary Site","volume":"16","author":"Keating S.","year":"2024","journal-title":"Cureus"},{"issue":"1","key":"e_1_2_11_3_1","article-title":"Epidemiology and Risk Factors of Melanoma: A Review","volume":"11","author":"Claudio C.","year":"2021","journal-title":"Dermatology Practical and Conceptual"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.suc.2019.09.005"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13671-020-00311-4"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0160485"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.54254\/2753-8818\/16\/20240599"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.2217\/imt-2016-0022"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.01.001"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2022.08.002"},{"key":"e_1_2_11_11_1","article-title":"Glycolytic Enzyme HK2 Promotes PD\u2010L1 Expression and Breast Cancer Cell Immune Evasion","volume":"14","author":"Jichun L.","year":"2023","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13402-023-00852-3"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-007146"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.17687"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.21147\/j.issn.1000-9604.2019.03.14"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2024.01.003"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-00820-7"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13578-023-01100-9"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3630"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20092085"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2025.106839"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1718-23.2024"},{"key":"e_1_2_11_23_1","doi-asserted-by":"crossref","unstructured":"V. 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