Autophagy-enhanced hybrid pyroptotic vesicles as personalized vaccines for cancer immunotherapy

Tumor vaccines represent a promising strategy for mobilizing the immune system against malignancies, however, their efficacy is limited by poor antigen immunogenicity, inefficient lymph nodes (LNs) accumulation, and inadequate antigen presentation by antigen-presenting cells (APCs), particularly dendritic cells (DCs). Pyroptosis, a pro-inflammatory form of cell death known to enhance immunogenicity, and autophagy, a cellular pathway that promotes MHC class I and II antigen presentation in APCs, have emerged as two compelling mechanisms to address these limitations. Here, we developed a biomimetic hybrid nanovaccine (hDMVac) by repeatedly extruding pyroptotic B16 and DC2.4, followed by loading with beclin-1. The results show that hDMVac exhibited a particle size of approximately 160 nm and showed enhanced accumulation in LNs after subcutaneous injection, with time-dependent distribution within the lymphatic system. The incorporation of pyroptotic tumor cells significantly enhanced antigen immunogenicity. Moreover, beclin-1 loading robustly induced autophagy in DCs, facilitating DCs maturation and markedly enhancing cross-presentation of antigens within LNs. The synergistic effect significantly amplified antigen-specific T cell activation. Consequently, hDMVac effectively suppressed tumor growth in both prophylactic and therapeutic melanoma models. This dual strategy represents a synergistic approach to overcoming the limitations of conventional tumor vaccines, representing a clinically translatable platform compatible with existing immunotherapies for improved tumor treatment.