Spatiotemporal Nano‐Regulator Unleashes Anti‐Tumor Immunity by Overcoming Dendritic Cell Tolerance and T Cell Exhaustion in Tumor‐Draining Lymph Nodes

Abstract Lymph nodes are crucial immune foci as the primary target for cancer immunotherapy. However, the anti‐tumor functions of tumor‐draining lymph nodes (TDLNs) are critically suppressed by tumors. Here, a novel spatiotemporal nano‐regulator is presented, designed to modulate the dendritic cells (DCs) in TDLNs, establishing a supportive niche for immune surveillance. The DC‐mediated nano‐regulator (DNR) is established by the self‐assembly of an imidazoquinoline (IMDQ) prodrug, inhibitory immune checkpoint (ICP) siRNA, and mannan (a TLR4 agonist). This unique design leverages the spatiotemporal activation of TLR4 and TLR7/8, thereby optimizing DC maturation and cytokine production. This further promotes efficient T cell priming. Simultaneously, the ICP‐targeting siRNA mitigates the tolerogenic effects induced by tumor‐derived factors and TLR activation, preventing T cell exhaustion. In essence, DNR facilitates potent remodeling of TDLNs and the tumor microenvironment, activating the anti‐tumor immunity cascade. When combined with vaccines, DNR greatly promotes tumor regression and the establishment of long‐term immunological memory.