In situ self-assembled glycopeptide regulates tumor microenvironment for tumor immunotherapy

The reprogramming of tumor-associated macrophages (TAMs) to antitumor phenotype has achieved considerable success in tumor immunotherapy. However, it remains challenging for current drugs to realize simultaneously repolarization and activation of TAMs. In this work, an in situ self-assembled glycopeptide was developed to regulate tumor microenvironment for tumor immunotherapy. Briefly, the in situ self-assembled glycopeptide selectively targets and anchors CD206/CD47 after intravenous injection, which rapidly transform into nanoclusters to repolarize protumoral M2-like TAMs to antitumoral M1-like through CD206 blockage and simultaneously enhance M1-like TAMs activation by CD47 occupancy. Enabled by in situ formed nanoclusters, the superior tumor retention capacity and accelerated blood clearance characteristics effectively mitigated the potential systemic toxicity of this transformable glycopeptide. Moreover, the glycopeptide realized significant repolarization and activation of TAMs in vitro and in vivo, which further induces effective antigen presentation and initiates T cell-mediated adaptive immune responses to inhibit tumor growth in various tumor models. This glycopeptide is endowed with multitargeted regulation and in situ transformation properties, inspiring the design of nanomedicines for tumor immunotherapy.