In situ formed reactive oxygen species-responsive dipyridamole prodrug hydrogel: Spatiotemporal drug delivery for chemoimmunotherapy.

In the realm of combined cancer immunotherapy, the strategic combination of therapeutics targeting both cancer cells and macrophages holds immense potential. However, the major challenges remain on how to achieve facile spatiotemporal delivery of these therapies, allowing ease of manipulation and ensuring differential drug release for enhanced synergistic therapeutic effects. In the present study, we introduced a tumor microenvironment (TME)-adapted hydrogel with the phenylboronic acid-modified dipyridamole prodrug (DIPP) as a crosslinker. This prodrug hydrogel scaffold, 3BP@DIPPGel, could be formed in situ by a simple mixture of DIPP and poly(vinyl alcohol) (PVA), and loaded with a high ratio of 3-bromopyruvic acid (3BP). The 3BP@DIPPGel enables spatiotemporal localized delivery of dipyridamole (DIP) and 3BP with distinct release kinetics that effectively reshape the immunosuppressive TME. Upon reactive oxygen species (ROS) stimulation, 3BP@DIPPGel preferentially released 3BP, inducing tumor-specific pyroptosis via the ROS/BAX/caspase-3/GSDME signaling pathway and decreasing the secretion of chemokines such as CCL8 to counteract macrophage recruitment. Subsequently, the crosslinked DIP is released, triggering the tumor-associated macrophages (TAMs) polarization towards the immunostimulatory M1 phenotype via the CCR2/JAK2/STAT3 cascade signaling pathway. This dual action from 3BP@DIPPGel leads to the restoration of tumor cell immunogenicity with high efficacy and activation of immune cells. Furthermore, the 3BP@DIPPGel-based chemoimmunotherapy upregulates the expression of sialic-acid-binding Ig-like lectin 10 and hence sensitizing tumors to anti-CD24 therapy in the tumor-bearing mice. Therefore, this strategy can have significant potential in the prevention of tumor metastases and recurrence. To the best of our understanding, this study represents a pioneering showcase of tumor pyroptosis, induced by glycolytic inhibitors, which can be effectively coordinated with DIP-mediated TAM polarization for immune activation, offering a new paradigm for differentially sustained drug delivery to foster cancer immunotherapy.