Annexin A5-engineered nanovaccines synchronize spatiotemporal antigen release with phagocytosis checkpoint blockade for potent in situ cancer immunotherapy.

Authors

Tianjiao Wang, Lu Wang, Xiaoying Kang, Junyan Jiang, Baohui Yuan, Lu Zhang, Xuya Yu, Ting Chen, Xueping Li, Yuan Zhang, Wen Meng, Jian Li, Ji Qi, Dan Ding, Yang Shi, Wen Li

Published in

Journal of controlled release : official journal of the Controlled Release Society. Pages 115460. Oct 16, 2026. Epub Oct 16, 2026.

Abstract

In situ generation of autologous tumor vaccines from dying tumor cells offers a promising route for personalized cancer immunotherapy, yet is often limited by phosphatidylserine (PS)-mediated immunosuppressive clearance that can restrict downstream immune activation and favor M2-like macrophage polarization. Here, we report a sequentially orchestrated nanovaccine (NT@ANX5-P) that couples photodynamic therapy (PDT)-induced immunogenic tumor-cell damage with on-demand PS masking to enhance in situ tumor vaccination. The nanovaccine consists of a photosensitizer core cloaked with genetically engineered tumor cell membranes displaying Annexin A5 (ANX5) and further shielded by a ROS-cleavable PEG layer for circulatory shielding and local light-responsive activation. Upon localized light irradiation, tumor cells undergo PDT-induced damage and apoptosis, while ROS-triggered PEG cleavage increases ANX5 accessibility for binding exposed PS, thereby attenuating PS-dependent efferocytic clearance and favoring progression toward secondary necrosis. This coordinated treatment enhanced dendritic cell maturation, remodeled tumor-associated macrophage phenotypes, and increased T-cell responses. In 4T1 tumor-bearing mice, NT@ANX5-P suppressed primary and distant tumor growth, reduced lung metastasis, and induced protection against homologous tumor rechallenge. CD8⁺ T-cell depletion markedly weakened bilateral tumor control, supporting an important functional contribution of CD8⁺ T cells. These findings provide proof-of-concept for coordinating PDT-induced antigen generation with spatially regulated modulation of PS-dependent dying-cell clearance in the 4T1 model.

PMID:
42887606
Bibliographic data and abstract were imported from PubMed on 17 Oct 2026.

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