{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T01:08:37Z","timestamp":1793236117591,"version":"4.5.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"crossref","award":["2024M751825"],"award-info":[{"award-number":["2024M751825"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-025-10952-9","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T15:09:32Z","timestamp":1752592172000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["TNFAIP2 deficiency drives formation of an immunosuppressive tumor microenvironment and confers resistance to anti-PD-1 therapy in skin cutaneous melanoma"],"prefix":"10.1038","volume":"15","author":[{"given":"Yaning","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinsong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiyang","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"key":"10952_CR1","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1001\/jamadermatol.2022.0160","volume":"158","author":"M Arnold","year":"2022","unstructured":"Arnold, M. et al. Global burden of cutaneous melanoma in 2020 and projections to 2040. JAMA Dermatol. 158, 495\u2013503. https:\/\/doi.org\/10.1001\/jamadermatol.2022.0160 (2022).","journal-title":"JAMA Dermatol."},{"key":"10952_CR2","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1016\/s0140-6736(23)00821-8","volume":"402","author":"GV Long","year":"2023","unstructured":"Long, G. V., Swetter, S. M., Menzies, A. M., Gershenwald, J. E. & Scolyer, R. A. Cutaneous melanoma. Lancet (London England)  402, 485\u2013502. https:\/\/doi.org\/10.1016\/s0140-6736(23)00821-8 (2023).","journal-title":"Lancet (London England)"},{"key":"10952_CR3","doi-asserted-by":"publisher","first-page":"21012","DOI":"10.1038\/s41598-021-00386-4","volume":"11","author":"TL Lee","year":"2021","unstructured":"Lee, T. L., Liao, Y. H., Liau, J. Y. & Sheen, Y. S. Risk factors of recurrence and distant metastasis in primary cutaneous melanoma in Taiwan. Sci. Rep. 11, 21012. https:\/\/doi.org\/10.1038\/s41598-021-00386-4 (2021).","journal-title":"Sci. Rep."},{"key":"10952_CR4","doi-asserted-by":"publisher","unstructured":"Xiao, Y. & Yu, D. Tumor microenvironment as a therapeutic target in cancer. Pharmacol. Ther. 221 https:\/\/doi.org\/10.1016\/j.pharmthera.2020.107753 (2021).","DOI":"10.1016\/j.pharmthera.2020.107753"},{"key":"10952_CR5","doi-asserted-by":"publisher","first-page":"3763","DOI":"10.1038\/s41467-019-11738-0","volume":"10","author":"Z Xiao","year":"2019","unstructured":"Xiao, Z., Dai, Z. & Locasale, J. W. Metabolic landscape of the tumor microenvironment at single cell resolution. Nat. Commun. 10, 3763. https:\/\/doi.org\/10.1038\/s41467-019-11738-0 (2019).","journal-title":"Nat. Commun."},{"key":"10952_CR6","doi-asserted-by":"publisher","first-page":"1212476","DOI":"10.3389\/fimmu.2023.1212476","volume":"14","author":"R Rui","year":"2023","unstructured":"Rui, R., Zhou, L. & He, S. Cancer immunotherapies: Advances and bottlenecks. Front. Immunol. 14, 1212476. https:\/\/doi.org\/10.3389\/fimmu.2023.1212476 (2023).","journal-title":"Front. Immunol."},{"key":"10952_CR7","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.trecan.2019.05.010","volume":"5","author":"GL Szeto","year":"2019","unstructured":"Szeto, G. L. & Finley, S. D. Integrative approaches to cancer immunotherapy. Trends Cancer 5, 400\u2013410. https:\/\/doi.org\/10.1016\/j.trecan.2019.05.010 (2019).","journal-title":"Trends Cancer"},{"key":"10952_CR8","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1016\/j.ccell.2019.02.008","volume":"35","author":"W Liao","year":"2019","unstructured":"Liao, W. et al. KRAS-IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer. Cancer Cell 35, 559\u2013572e557. https:\/\/doi.org\/10.1016\/j.ccell.2019.02.008(2019).","journal-title":"Cancer Cell."},{"key":"10952_CR9","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.cell.2023.11.037","volume":"187","author":"J Pozniak","year":"2024","unstructured":"Pozniak, J. et al. A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma. Cell 187, 166\u2013183e125. https:\/\/doi.org\/10.1016\/j.cell.2023.11.037 (2024).","journal-title":"Cell"},{"key":"10952_CR10","first-page":"1824","volume":"60","author":"ME Rusiniak","year":"2000","unstructured":"Rusiniak, M. E., Yu, M., Ross, D. T., Tolhurst, E. C. & Slack, J. L. Identification of B94 (TNFAIP2) as a potential retinoic acid target gene in acute promyelocytic leukemia. Cancer Res. 60, 1824\u20131829 (2000).","journal-title":"Cancer Res."},{"key":"10952_CR11","doi-asserted-by":"publisher","first-page":"2040","DOI":"10.1038\/onc.2015.263","volume":"35","author":"L Jia","year":"2016","unstructured":"Jia, L. et al. KLF5 promotes breast cancer proliferation, migration and invasion in part by upregulating the transcription of TNFAIP2. Oncogene 35, 2040\u20132051. https:\/\/doi.org\/10.1038\/onc.2015.263 (2016).","journal-title":"Oncogene"},{"key":"10952_CR12","doi-asserted-by":"publisher","first-page":"3648","DOI":"10.1038\/onc.2013.345","volume":"33","author":"CC Chen","year":"2014","unstructured":"Chen, C. C. et al. NF-\u03baB-mediated transcriptional upregulation of TNFAIP2 by the Epstein-Barr virus oncoprotein, LMP1, promotes cell motility in nasopharyngeal carcinoma. Oncogene 33, 3648\u20133659. https:\/\/doi.org\/10.1038\/onc.2013.345 (2014).","journal-title":"Oncogene"},{"key":"10952_CR13","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1186\/s13046-023-02775-1","volume":"42","author":"T Xu","year":"2023","unstructured":"Xu, T. et al. TNFAIP2 confers cisplatin resistance in head and neck squamous cell carcinoma via KEAP1\/NRF2 signaling. J. Experimental Clin. cancer Research: CR. 42, 190. https:\/\/doi.org\/10.1186\/s13046-023-02775-1 (2023).","journal-title":"J. Experimental Clin. cancer Research: CR"},{"key":"10952_CR14","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/s12964-025-02077-3","volume":"23","author":"T Xu","year":"2025","unstructured":"Xu, T. et al. TNFAIP2 promotes NF-\u03baB signaling mediate lymph node metastasis of oral squamous cell carcinoma by protecting IKK\u03b2 from ubiquitin proteasome degradation. Cell. Communication Signaling: CCS. 23, 83. https:\/\/doi.org\/10.1186\/s12964-025-02077-3 (2025).","journal-title":"Cell. Communication Signaling: CCS"},{"key":"10952_CR15","doi-asserted-by":"publisher","first-page":"567730","DOI":"10.3389\/fmolb.2021.567730","volume":"8","author":"Y Wang","year":"2021","unstructured":"Wang, Y., Chen, Y., Zhu, B., Ma, L. & Xing, Q. A. Novel nine apoptosis-related genes signature predicting overall survival for kidney renal clear cell carcinoma and its associations with immune infiltration. Front. Mol. Biosci. 8, 567730. https:\/\/doi.org\/10.3389\/fmolb.2021.567730 (2021).","journal-title":"Front. Mol. Biosci."},{"key":"10952_CR16","doi-asserted-by":"publisher","unstructured":"Hou, C. et al. Targeting TNFAIP2 induces immunogenic cell death and sensitizes glioblastoma multiforme to anti-PD-1 therapy. J. Neuro-Oncol. 165, 79\u201390. https:\/\/doi.org\/10.1007\/s11060-023-04449-6 (2023).","DOI":"10.1007\/s11060-023-04449-6"},{"key":"10952_CR17","doi-asserted-by":"publisher","first-page":"W214","DOI":"10.1093\/nar\/gkq537","volume":"38","author":"D Warde-Farley","year":"2010","unstructured":"Warde-Farley, D. et al. The genemania prediction server: Biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 38, W214\u2013W220. https:\/\/doi.org\/10.1093\/nar\/gkq537 (2010).","journal-title":"Nucleic Acids Res."},{"key":"10952_CR18","doi-asserted-by":"publisher","first-page":"2871","DOI":"10.1111\/cas.15818","volume":"114","author":"Q Gou","year":"2023","unstructured":"Gou, Q. et al. PPAR\u03b3 inhibited tumor immune escape by inducing PD-L1 autophagic degradation. Cancer Sci. 114, 2871\u20132881. https:\/\/doi.org\/10.1111\/cas.15818 (2023).","journal-title":"Cancer Sci."},{"key":"10952_CR19","doi-asserted-by":"publisher","unstructured":"Jiang, X. et al. Role of the tumor microenvironment in PD-L1\/PD-1-mediated tumor immune escape. Mol. Cancer 18 https:\/\/doi.org\/10.1186\/s12943-018-0928-4 (2019).","DOI":"10.1186\/s12943-018-0928-4"},{"key":"10952_CR20","doi-asserted-by":"publisher","first-page":"3633","DOI":"10.1016\/S0021-9258(17)41909-0","volume":"269","author":"FW Wolf","year":"1994","unstructured":"Wolf, F. W. et al. B94, a primary response gene inducible by tumor necrosis factor-alpha, is expressed in developing hematopoietic tissues and the sperm acrosome. J. Biol. Chem. 269, 3633\u20133640 (1994).","journal-title":"J. Biol. Chem."},{"key":"10952_CR21","doi-asserted-by":"publisher","unstructured":"Fang, H. et al. Integrin \u03b24 promotes DNA damage-related drug resistance in triple-negative breast cancer via TNFAIP2\/IQGAP1\/RAC1. eLife 12. https:\/\/doi.org\/10.7554\/eLife.88483 (2023).","DOI":"10.7554\/eLife.88483"},{"key":"10952_CR22","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1038\/nrc.2016.54","volume":"16","author":"C Engblom","year":"2016","unstructured":"Engblom, C., Pfirschke, C. & Pittet, M. J. The role of myeloid cells in cancer therapies. Nat. Rev. Cancer 16, 447\u2013462. https:\/\/doi.org\/10.1038\/nrc.2016.54 (2016).","journal-title":"Nat. Rev. Cancer"},{"key":"10952_CR23","doi-asserted-by":"publisher","first-page":"2394","DOI":"10.1084\/jem.20182124","volume":"216","author":"A Etzerodt","year":"2019","unstructured":"Etzerodt, A. et al. Specific targeting of CD163(+) TAMs mobilizes inflammatory monocytes and promotes T cell-mediated tumor regression. J. Exp. Med. 216, 2394\u20132411. https:\/\/doi.org\/10.1084\/jem.20182124 (2019).","journal-title":"J. Exp. Med."},{"key":"10952_CR24","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1016\/j.cell.2020.03.048","volume":"181","author":"L Zhang","year":"2020","unstructured":"Zhang, L. et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell 181, 442\u2013459e429. https:\/\/doi.org\/10.1016\/j.cell.2020.03.048 (2020).","journal-title":"Cell"},{"key":"10952_CR25","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1016\/j.jhep.2023.08.024","volume":"79","author":"Y Meng","year":"2023","unstructured":"Meng, Y. et al. Immunosuppressive CD10(+)ALPL(+) neutrophils promote resistance to anti-PD-1 therapy in HCC by mediating irreversible exhaustion of T cells. J. Hepatol. 79, 1435\u20131449. https:\/\/doi.org\/10.1016\/j.jhep.2023.08.024 (2023).","journal-title":"J. Hepatol."},{"key":"10952_CR26","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1158\/2159-8290.Cd-19-0074","volume":"9","author":"M de Ruiz","year":"2019","unstructured":"de Ruiz, M. et al. \u03b2-catenin activation promotes immune escape and resistance to Anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 9, 1124\u20131141. https:\/\/doi.org\/10.1158\/2159-8290.Cd-19-0074 (2019).","journal-title":"Cancer Discov."},{"key":"10952_CR27","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1038\/s41590-019-0441-y","volume":"20","author":"V Verma","year":"2019","unstructured":"Verma, V. et al. PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1(+)CD38(hi) cells and anti-PD-1 resistance. Nat. Immunol. 20, 1231\u20131243. https:\/\/doi.org\/10.1038\/s41590-019-0441-y (2019).","journal-title":"Nat. Immunol."},{"key":"10952_CR28","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1016\/j.ccell.2023.02.005","volume":"41","author":"JD Klement","year":"2023","unstructured":"Klement, J. D. et al. Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment. Cancer Cell. 41, 620\u2013636e629. https:\/\/doi.org\/10.1016\/j.ccell.2023.02.005 (2023).","journal-title":"Cancer Cell."},{"key":"10952_CR29","doi-asserted-by":"publisher","first-page":"6858","DOI":"10.1038\/s41467-023-42634-3","volume":"14","author":"H Wu","year":"2023","unstructured":"Wu, H. et al. Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1\u03b1-mediated glycolytic reprogramming. Nat. Commun. 14, 6858. https:\/\/doi.org\/10.1038\/s41467-023-42634-3 (2023).","journal-title":"Nat. Commun."},{"key":"10952_CR30","doi-asserted-by":"publisher","unstructured":"Fu, J. et al. Large-scale public data reuse to model immunotherapy response and resistance. Genome Med. 12 https:\/\/doi.org\/10.1186\/s13073-020-0721-z (2020).","DOI":"10.1186\/s13073-020-0721-z"}],"updated-by":[{"DOI":"10.1038\/s41598-025-26656-z","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,11,16]],"date-time":"2025-11-16T00:00:00Z","timestamp":1763251200000}}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-10952-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-10952-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-10952-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T11:02:55Z","timestamp":1763377375000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-10952-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,15]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["10952"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-10952-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,15]]},"assertion":[{"value":"28 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 November 2025","order":5,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":6,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41598-025-26656-z","URL":"https:\/\/doi.org\/10.1038\/s41598-025-26656-z","order":8,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"<!--Emphasis Type='Bold' removed-->Supplementary information"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Our research was conducted in accordance with the Declaration of Helsinki (as revised in 2013) with informed consent signed by all incorporated patients. Our animal experiments were approved by the Ethic Committee of the Second Hospital of Shandong University (No. KYLL2023016) and conducted in accordance with the institutional guidelines and regulations. The study was carried out in compliance with the ARRIVE guidelines.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}}],"article-number":"25569"}}