Multimodal Regulation of Dendritic Cells via Mineralized Vaccines for Postsurgical Tumor Relapse Prevention.

Abstract

The regulation of dendritic cell (DC) function is pivotal for augmenting the immune response of traditional tumor therapy, particularly in mitigating postsurgical tumor relapse. Unfortunately, DC functionality is often compromised in the postsurgical microenvironment, leading to immune tolerance and tumor progression. To address these challenges, we developed a personalized cancer vaccine, Cell@CaP, which utilizes inactivated autologous tumor cells coated with a calcium phosphate shell. This innovative vaccine incorporates cyclic GMP-AMP (cGAMP), a STING agonist, and calcium ions (Ca²⁺) to boost DCs activation and antigen presentation. The Cell@CaP vaccine leverages high mechanical hardness, intact tumor antigens, and the release of cGAMP and Ca²⁺ to activate DCs through multiple pathways. Upon interaction with DCs, the vaccine triggers the Piezo1 mechanosensitive channel, inducing a Ca²⁺ influx. This mechanical stimulation, combined with the release of cGAMP and tumor antigens, activates the cGAS-STING, PI3K-Akt, and RhoA-MYPT1 signaling pathways. These synergistic effects enhance the expression of costimulatory molecules and promote the secretion of pro-inflammatory cytokines (interferon-β and tumor necrosis factor-α). In a postsurgical osteosarcoma model, the combination of Cell@CaP with radiotherapy significantly inhibited primary tumor relapse and suppressed distant lung metastases. This multimodal vaccine strategy integrates mechanical, chemical, and immunological cues into a single platform, offering a promising approach to enhance DCs functionality and activate robust antitumor immunity. The study highlights the potential of Cell@CaP as a personalized immunotherapy for preventing postsurgical tumor relapse.