Immunogenic cell death-primed autophagosome vaccines drive dendritic cell cross-presentation and suppress colon cancer metastasis

Immunogenic cell death (ICD) releases tumor-associated antigens and damage-associated molecular patterns (DAMPs) but also generates substantial suppressive by-products that limit the translation of ICD-based Cancer vaccines into effective therapies. The research bottleneck lies in how to selectively enrich these ICD-derived immunogenic substances and efficiently deliver them to the most potent antigen cross-presenting dendritic cells (cDC1), thereby priming CD8⁺ T cell immunity. By leveraging the natural Autophagy process within cells, this study presents an ICD-Primed Autophagosome Engineering strategy to harvest immunogenic cargo-containing autophagosomes (ICAPs) that co-enrich tumor-associated antigens and DAMPs while depleting inhibitory components. Mechanistically, F-actin exposure on ICAPs licenses DNGR-1 (CLEC9A)-dependent recognition by cDC1, promoting efficient uptake and cross-presentation. ICAP-based immunotherapy biases toward robust CD8⁺ T cell responses and achieves ∼90% tumor clearance in a peritoneal metastasis mouse model. Simultaneously, ICAPs-mediated lysosomal escape potentiates CpG-TLR9 signaling, creating an amplification of adaptive immunity and significantly enhancing therapeutic efficacy against colon Cancer liver metastasis. By coupling ICD-driven content generation with autophagosomal co-loading, this work positions autophagosomes as selective, endogenous cargo concentrators and provides a scalable path toward personalized vaccines against metastasis and minimal residual disease.

Autophagosome; Cancer immunotherapy; Colorectal cancer; Immunogenic cell death.