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Cigarette smoke is an environmental exposure promoting progression of NSCLC, but its role is poorly understood. This study reports that smoking\u2010induced accumulation of M2\u2010type tumor\u2010associated macrophages (M2\u2010TAMs) surrounding NSCLC tissues promotes malignancy. Specifically, extracellular vesicles (EVs) from cigarette smoke extract (CSE)\u2010induced M2 macrophages promoted malignancy of NSCLC cells in vitro and in vivo. circEML4 in EVs from CSE\u2010induced M2 macrophages is transported to NSCLC cells, where it reduced the distribution of ALKBH5 in the nucleus by interacting with Human AlkB homolog H5 (ALKBH5), resulting in elevated N6\u2010methyladenosine (m6A) modifications. m6A\u2010seq and RNA\u2010seq revealed suppressor of cytokine signaling 2 (SOCS2)\u2010mediated activation of the Janus kinase\u2010signal transducer and activator of transcription (JAK\u2010STAT) pathway by regulating m6A modification of SOCS2 via ALKBH5. Down\u2010regulation of circEML4 in EVs from CSE\u2010induced M2 macrophages reversed EVs\u2010enhanced tumorigenicity and metastasis in NSCLC cells. Furthermore, this study found that smoking patients showed an increase in circEML4\u2010positive M2\u2010TAMs. These results indicate that smoking\u2010induced M2\u2010TAMs via circEML4 in EVs promote the NSCLC progression through ALKBH5\u2010regulated m6A modification of SOCS2. This study also reveals that circEML4 in EVs from TAMs acts as a diagnostic biomarker for NSCLC, especially for patients with smoking history.<\/jats:p>","DOI":"10.1002\/advs.202300953","type":"journal-article","created":{"date-parts":[[2023,5,28]],"date-time":"2023-05-28T23:47:00Z","timestamp":1685317620000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Smoking\u2010Induced M2\u2010TAMs, via circEML4 in EVs, Promote the Progression of NSCLC through ALKBH5\u2010Regulated m6A Modification of SOCS2 in NSCLC Cells"],"prefix":"10.1002","volume":"10","author":[{"given":"Cheng","family":"Cheng","sequence":"first","affiliation":[{"name":"Center for Global Health The Key Laboratory of Modern Toxicology Ministry of Education School of Public Health Suzhou Institute of Public Health Gusu School Nanjing Medical University  Nanjing Jiangsu 211166 P. R. 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