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Nanomedicines (NMs) offer novel therapeutic strategies for reversing the immunosuppressive TME in LC. This review systematically analysed the diverse mechanisms contributing to immunosuppressive TME formation and explored the potential of smart responsive NMs in targeted drug delivery, immune remodeling, and multimodal therapy. The immunosuppressive TME in LC arises from abnormal physiological conditions, extracellular matrix (ECM) deposition, dysfunction of antigen\u2010presenting cells, exhaustion of T cells, infiltration of immunosuppressive cells, metabolic reprogramming, and microbiota influences. Smart NMs can overcome delivery barriers through passive targeting and ligand\u2010directed active targeting to LC cells via receptors, as well as to immunosuppressive cell populations. NMs can respond to endogenous and exogenous stimuli, enabling precise spatiotemporal drug release. This feature enables integration of chemotherapy, immunotherapy, and physical therapies. Additionally, NMs can reprogram the TME by remodeling physiological conditions, inhibiting ECM deposition, regulating metabolism, inducing immunogenic cell death, and modulating microbiota\u2010derived metabolites. Although toxicity and clinical translation still require further optimization, smart NMs offer a paradigm shift for LC therapy through an integrated \u201ctargeted delivery\u2010immune reprogramming\u201d strategy.<\/jats:p>","DOI":"10.1002\/advs.202518487","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T12:05:15Z","timestamp":1762517115000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The Immune Microenvironment in Liver Cancer: From Analysis to Targeting"],"prefix":"10.1002","volume":"12","author":[{"given":"Jiaming","family":"Lan","sequence":"first","affiliation":[{"name":"Department of Interventional Radiology Shengjing Hospital of China Medical University  Shenyang Liaoning 110004 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Li","sequence":"additional","affiliation":[{"name":"China Medical University  Shenyang Liaoning 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Interventional Radiology Shengjing Hospital of China Medical University  Shenyang Liaoning 110004 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yourong","family":"Duan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes Shanghai Cancer Institute Renji Hospital School of Medicine Shanghai Jiao Tong University  Shanghai 200032 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Sun","sequence":"additional","affiliation":[{"name":"Wuya College of Innovation Shenyang Pharmaceutical University  Shenyang Liaoning 110016 China"},{"name":"Joint International Research Laboratory of Intelligent Drug Delivery Systems Ministry of Education   Shenyang Liaoning 110016 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6528-8522","authenticated-orcid":false,"given":"Meng","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Interventional Radiology Shengjing Hospital of China Medical University  Shenyang Liaoning 110004 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,7]]},"reference":[{"key":"e_1_2_14_1_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.18"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)01200-4"},{"key":"e_1_2_14_5_1","author":"Ping L.","year":"2008","journal-title":"China Pharmacy"},{"key":"e_1_2_14_6_1","first-page":"940","volume":"19","author":"Zhu A. 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