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The liver, characterized by its immune-tolerant landscape and dense population of phagocytic cells, suppresses antitumor responses in hepatocellular carcinoma (HCC). Meanwhile, the lungs\u2019 vast vasculature and continuous exposure to airborne antigens necessitate precision delivery strategies to trigger robust immunity without provoking excessive inflammation. To surmount these hurdles, nanocarriers have been engineered to leverage passive targeting through the enhanced permeability and retention (EPR) effect, active targeting via organ-specific ligands, immune cell hitchhiking, and stimuli-responsive release mechanisms. These innovations enable nanovaccines to elicit localized immune activation, reshape the tumor microenvironment (TME), and enhance cytotoxic T-cell responses. This review underscores the critical importance and urgent need for continued development of organ-specific nanovaccine platforms. It calls for intensified research efforts to translate these technologies into clinically viable therapies capable of addressing the most immunologically challenging tumor sites.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical Abstract<\/jats:bold>\n          <\/jats:p>","DOI":"10.1007\/s13346-025-01935-4","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T12:19:45Z","timestamp":1754914785000},"page":"4217-4259","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Beyond borders: engineering organ-targeted immunotherapies to overcome site-specific barriers in cancer"],"prefix":"10.1007","volume":"15","author":[{"given":"Thrinayan","family":"Moorthy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhanu Nirosha","family":"Yalamandala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thi My Hue","family":"Huynh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Wen","family":"Lien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Chi","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoi Man","family":"Iao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Hsuan","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8965-3918","authenticated-orcid":false,"given":"Shang-Hsiu","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,11]]},"reference":[{"key":"1935_CR1","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1021\/acs.bioconjchem.4c00287","volume":"35","author":"X Chai","year":"2024","unstructured":"Chai X, Zhang Y, Zhang W, Feng K, Jiang Y, Zhu A, et al. 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