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

作者：Ruonan Wang, Huixin Li, Shasha He, Yuanji Feng, Cong Liu, Kai Hao, Danhua Zhou, Xiaoyuan Chen, Huayu Tian · 发表于：Advanced Materials · 年份：2024 · DOI：10.1002/adma.202412141 · 被引用次数：19 · 研究领域：Immunotherapy and Immune Responses、Cancer Immunotherapy and Biomarkers、Nanoplatforms for cancer theranostics

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.