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Conventional tumor vaccines fail in PAAD due to a suppressive tumor microenvironment (TME), inadequate antigen presentation, and impaired immunogenic cell death (ICD). Using a machine learning\u2010driven transcriptomic analysis, we identified FSTL3 as a vital TME regulatory factor enriched in desmoplastic pancreatic lesions and constructed a cRGD\u2010modified liposomal carrier co\u2010encapsulating gemcitabine and siFSTL3 (siFSTL3\/Lip\n                    <jats:sub>GEM<\/jats:sub>\n                    \u2010cRGD). Unlike antigen\u2010preloaded conventional nanovaccines, this liposome acts as an irradiation\u2010activated inducer of in situ tumor vaccination. This engineered multifunctional nanovaccine enhanced radiochemosensitivity and, combined with ionizing radiation (IR), promoted dendritic cell maturation, ICD, and ferroptosis. Mechanistically, this composite nanovaccine synergized with IR to trigger ferroptosis and ICD via the STAT1\u2010IRF1\u2010ACSL4 axis, thereby remodeling the TME and overcoming the limitations of conventional vaccines by enhancing antigen release. In vivo, triple therapy with the liposomal carrier, IR, and anti\u2010PD\u2010L1 achieves robust anti\u2010tumor activity with negligible systemic toxicity and overcomes immune checkpoint blockade resistance. This study develops a translatable radiotherapy\u2010initiated in situ nanovaccination strategy relying on synergistic ferroptosis and ICD to treat refractory PAAD.\n                  <\/jats:p>","DOI":"10.1002\/advs.77651","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T04:22:00Z","timestamp":1789100520000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multifunctional Nanovaccine\u2010Radiotherapy Synergy Drives Anti\u2010Tumor Immunity via Multi\u2010Cascade Cell Death for Pancreatic Cancer Therapy"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3717-4939","authenticated-orcid":false,"given":"Chengyi","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology Changhai Hospital affiliated to Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yushu","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Changhai Hospital affiliated to Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5964-9248","authenticated-orcid":false,"given":"Xiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Oncology Zhujiang Hospital Southern Medical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanhao","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5769-9308","authenticated-orcid":false,"given":"Xiaofei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Changhai Hospital affiliated to Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Changhai Hospital affiliated to Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyang","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Changhai Hospital affiliated to Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Changhai Hospital affiliated to Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Changhai Hospital affiliated to Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7839-4183","authenticated-orcid":false,"given":"Zhenyuan","family":"Miao","sequence":"additional","affiliation":[{"name":"School of Pharmacy Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0872-2956","authenticated-orcid":false,"given":"Bufu","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Interventional Radiology Shanghai Institute of Medical Imaging Shanghai Institution of Medical Imaging Zhongshan Hospital, Shanghai National Clinical Research Center of Interventional Medicine Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4327-3498","authenticated-orcid":false,"given":"Huojun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Changhai Hospital affiliated to Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"e_1_2_10_2_1","first-page":"12","article-title":"Cancer Statistics, 2024","volume":"74","author":"Siegel R. 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