Chitosan-based hydrogel facilitates DC-SIGN-mediated monocyte-to-dendritic cell transformation in vivo for antigen-specific antitumor therapy

In vivo-generated monocyte-derived dendritic cells (moDCs) play a pivotal role in inducing effective immune responses against infections and Cancer due to their exceptional cross-presentation capabilities. However, the in vivo generation of moDCs during immunotherapy is constrained by the absence of safe and efficient in vivo strategies. Here, we propose a chitosan oligosaccharide-based CaCO₃ nanoparticle-loaded hydrogel (CCH) to facilitate effective in vivo monocyte-to-moDC conversion by leveraging its in-situ spatiotemporal regulation capabilities. The CCH promotes the secretion of chemokines to recruit monocytes and then targets a dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN)-pathway to facilitate the differentiation of monocytes into moDCs within a subcutaneous immune niche formed by CCH. After the removal of DC-SIGN⁺ cells in DC-SIGN-DTR mice, the proportion of CCH-induced moDCs significantly decreased, indicating the DC-SIGN-dependent conversion of moDCs. Accordingly, the tumor cell loaded-CCH (TCH)-induced moDCs facilitate cross-presentation to prime T cells and enhance robust antitumor T cell memory responses. Thus, subcutaneous injection of TCH effectively prevent the growth of primary liver Cancer and patient-derived xenograft (PDX) colorectal Cancer. Moreover, TCH inhibits postoperative tumor recurrence, providing promising advancements in immunotherapy. Our CCH-based strategy provided important insights on how to in vivo induce moDCs to harness cross-presentation for anti-tumor therapy.

Chitosan hydrogel; DC-SIGN; Monocyte-to-moDCs conversion; Primary liver cancer model.