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However, the environmental cues that govern TAM differentiation and immunosuppressive activity remain incompletely understood. Here we demonstrate that hepatocellular carcinoma (HCC) cells secrete extracellular vesicles (EVs) that are preferentially taken up by monocytes, inducing their differentiation to TAMs characterized by a distinct immune\u2010inhibitory signature. Mechanistically, HCC\u2010derived EVs encapsulate the lipogenic enzyme ATP\u2010citrate lyase (ACLY), promote palmitate biosynthesis in targeted monocytes, thereby enhancing the S\u2010palmitoylation and stability of multiple immune checkpoint proteins. To validate this, we synthesized liposomal vesicles (LVs) decorated with an EV\u2010marker protein CD81, which mimicked the targeting specificity of endogenous EVs for monocytes and differentiated macrophages. When loaded with ACLY proteins as interior cargo, these LVs were sufficient to induce immunosuppressive TAMs and promote HCC progression. Conversely, CD81\u2010decorated LVs encapsulating the ACLY inhibitor SB204990 markedly reduced the TAM\u2010mediated immunosuppressive activity, leading to restrained HCC progression. Importantly, we further demonstrated that targeting EV\u2010transferred, TAM\u2010specific ACLY represents a promising strategy to enhance immunotherapeutic efficacy without notable side effects, particularly when combined with anti\u2010PD\u20101\/PD\u2010L1 antibodies for HCC treatment.<\/jats:p>","DOI":"10.1002\/advs.202521458","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T11:39:57Z","timestamp":1776425997000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Extracellular Vesicle\u2010Transferred ATP\u2010Citrate Lyase Induces Monocyte Differentiation Toward Tumor\u2010Associated Macrophages and Fuels Hepatocellular Carcinoma Progression"],"prefix":"10.1002","volume":"13","author":[{"given":"Zhijun","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Multi\u2010organ Injury Prevention and Treatment Department of Biochemistry and Molecular 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