Carbon Dot-Linked Hydrogel for TAMs Transform: Spatiotemporal Manipulation to Reshape Tumor Microenvironment

As one of the most crucial immune cells in the tumor microenvironment (TME), regulating tumor-associated macrophages (TAMs) is vital for enhancing antitumor immunity. Here, an injectable carbon dots (CDs)-linked egg white hydrogel was developed, termed TAMs Transform Factory (TTF-L-C), to spatiotemporally manipulate TAMs. The fabricated CDs significantly promoted macrophage migration. Notably, TTF-L-C achieved macrophage spatial enrichment through CDs-induced directional recruitment with molecular Ctnnd1 upregulation. Subsequently, the recruited macrophages were locoregionally reprogrammed within TTF-L-C, as well as blocking the upregulated PD-L1. Finally, through multi-stage regulation at spatial, cellular, and molecular levels, TTF-L-C released immune-activated M1 macrophages to the tumor site as it degraded. Moreover, TTF-L-C promoted dendritic cell (DCs) maturation and further boosted T cell activation, thereby reshaping the tumor-suppressive TME. Through peritumoral injection, TTF-L-C enhanced tumor immunotherapy in both subcutaneous and recurrent 4T1 tumor models with satisfactory biosafety. Therefore, TTF-L-C is proposed to become a safe and powerful platform for various biomedical applications.