Multifunctional Nanovaccine-Radiotherapy Synergy Drives Anti-Tumor Immunity via Multi-Cascade Cell Death for Pancreatic Cancer Therapy.

Pancreatic adenocarcinoma (PAAD) is an immunosuppressive malignancy refractory to radiotherapy and immunotherapy. 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-driven transcriptomic analysis, we identified FSTL3 as a vital TME regulatory factor enriched in desmoplastic pancreatic lesions and constructed a cRGD-modified liposomal carrier co-encapsulating gemcitabine and siFSTL3 (siFSTL3/LipGEM-cRGD). Unlike antigen-preloaded conventional nanovaccines, this liposome acts as an irradiation-activated 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-IRF1-ACSL4 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-PD-L1 achieves robust anti-tumor activity with negligible systemic toxicity and overcomes immune checkpoint blockade resistance. This study develops a translatable radiotherapy-initiated in situ nanovaccination strategy relying on synergistic ferroptosis and ICD to treat refractory PAAD.