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In our study, we identified a lactate-based chemical barrier surrounding FAP<jats:sup>+<\/jats:sup> cancer-associated fibroblasts (CAFs) within the LUAD microenvironment (TME), which may hinder the infiltration and function of CD8<jats:sup>+<\/jats:sup> T cells. Further investigation revealed that FAP<jats:sup>+<\/jats:sup> CAFs specifically overexpress LINC01711, which drives lactate production by promoting FGFR1-mediated phosphorylation of lactic dehydrogenase A (LDHA) at the Y10 site and facilitating the formation of active LDHA tetramers. These FAP<jats:sup>+<\/jats:sup> CAFs then export lactate into TME via the MCT4 transporter, thereby establishing a chemical barrier and fostering an immunosuppressive TME. Notably, we developed a small extracellular vesicle (sEV)-based in vivo self-assembled siRNA system for in vivo knockdown of LINC01711 and demonstrated its potential to enhance the response rate to ICIs in LUAD. Our findings underscore the pivotal role of FAP<jats:sup>+<\/jats:sup> CAFs in driving resistance to ICIs and propose novel therapeutic strategies to overcome this obstacle.<\/jats:p>","DOI":"10.1038\/s41419-025-07974-6","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T03:38:10Z","timestamp":1756093090000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Targeting LINC01711 in FAP+ cancer-associated fibroblasts overcomes lactate-mediated immunosuppression and enhances anti-PD-1 efficacy in lung adenocarcinoma"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0876-8551","authenticated-orcid":false,"given":"Qinglin","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhizong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangwei","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijun","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanchen","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6923-8338","authenticated-orcid":false,"given":"Ziyang","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyang","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6490-1471","authenticated-orcid":false,"given":"Lin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5807-4219","authenticated-orcid":false,"given":"Xi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongyan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9744-4251","authenticated-orcid":false,"given":"Rong","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"7974_CR1","doi-asserted-by":"publisher","first-page":"1999","DOI":"10.1200\/JCO.22.01990","volume":"41","author":"S Novello","year":"2023","unstructured":"Novello S, Kowalski DM, Luft A, G\u00fcm\u00fc\u015f M, Vicente D, Mazi\u00e8res J, et al. 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Specifically, animal studies were approved by the Institutional Animal Care and Use Committee of Nanjing Medical University (No. IACUC-2020129). All animal studies were complied with the ARRIVE guidelines and were conducted in accordance with the UK Animals (Scientific Procedures) Act, 1986 and associated guidelines, EU Directive 2010\/63\/EU for animal experiments, or the National Institutes of Health Guide for the care and use of Laboratory animals (NIH Publications No. 8023, revised 1978). Experiments involving humans were in accordance with the ethical standards of the committee (institution and national) and with The Code of Ethics of the World Medical Association (Declaration of Helsinki). All patients completed written informed consent prior to study entry. This study protocol was reviewed and approved by the Ethics Committee of Jiangsu Cancer Hospital, located in Nanjing, Jiangsu Province, China.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"Each patient\u2019s consent form has been signed.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Patient consent"}}],"article-number":"642"}}