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

Abstract 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.