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Single\u2010cell RNA sequencing (scRNA\u2010seq) has revealed senescent Kupffer cells (sKCs), which are characterized by high levels of\n                    <jats:italic>p21<\/jats:italic>\n                    expression and enriched in the tumor microenvironment (TME) of HCC\u2010PVTT. These sKCs exhibit a pronounced senescence\u2010associated secretory phenotype (SASP), promoting the proliferation and invasion of tumors and crosstalk with cancer\u2010associated fibroblasts. To target sKCs, a biomimetic nanodelivery system termed SKEV@AAV has been developed. This system comprises adeno\u2010associated virus (AAV) vectors carrying\n                    <jats:italic>p21<\/jats:italic>\n                    \u2010specific shRNA, encapsulated within sKCs\u2010derived exosomes (SKEV). SKEV@AAV effectively downregulated\n                    <jats:italic>p21<\/jats:italic>\n                    , suppressed SASP signaling, and disrupted pro\u2010tumor interactions between sKCs and cancer\u2010associated fibroblasts. In an orthotopic PVTT model, SKEV@AAV showed single\u2010agent antitumor activity and attenuated SASP\u2010associated inflammatory remodeling. Furthermore, the combination efficacy with anti\u2010PD\u20101 was evaluated in a murine splenic liver\u2010metastasis model, where SKEV@AAV reduced tumor burden, enhanced CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cell infiltration, decreased regulatory T cells, and promoted memory T\u2010cell differentiation. Our findings reveal a pivotal role of sKCs in mediating immune suppression in HCC\u2010PVTT and provide a nanotherapeutic strategy that reverses sKCs' senescence, reprograms the TME, and ultimately enhances antitumor immune activation.\n                  <\/jats:p>","DOI":"10.1002\/advs.76384","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T09:36:44Z","timestamp":1782985004000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting\n                    <i>p21<\/i>\n                    \u2010High Senescent Kupffer Cells Nanotherapeutically Potentiates Antitumor Immunity in Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombus"],"prefix":"10.1002","volume":"13","author":[{"given":"Na","family":"Ta","sequence":"first","affiliation":[{"name":"Department of Medical Oncology The First Hospital of China Medical University  Shenyang P. R. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3814-8492","authenticated-orcid":false,"given":"Tao","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology The First Hospital of China Medical University  Shenyang P. R. 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