cGAS-STING pathway is a key DNA-sensing machinery and emerges as a promising target to overcome the immunoresistance of solid tumors. Here we describe a bovine serum albumin (BSA)/ferritin-based nanoagonist incorporating manganese (II) ions and β-lapachone, which cooperatively activates cGAS-STING signaling in dendritic cells (DCs) to elicit robust adaptive antitumor immunity. Mn²⁺-anchored mannose-modified BSAs and β-lapachone-loaded ferritins are crosslinked to afford bioresponsive protein nanoassemblies, which dissociate into monodispersive protein units in acidic perivascular tumor microenvironment (TME), thus enabling enhanced tumor penetration and spatiotemporally controlled Mn²⁺ and β-lapachone delivery to DCs and tumor cells, respectively. β-lapachone causes immunogenic tumor cell apoptosis and releases abundant dsDNA into TME, while Mn²⁺ enhances the sensitivity of cGAS to dsDNA and augments STING signaling to trigger downstream immunostimulatory signals. The cGAS-STING nanoagonist enhances the tumor-specific T cell-mediated immune response against poorly immunogenic solid tumors in vivo, offering a robust approach for immunotherapy in the clinics.

cGAS-STING 通路是一种关键的 DNA 传感机制，并成为克服实体瘤免疫抗性的有希望的靶标。在这里，我们描述了一种基于牛血清白蛋白 (BSA)/铁蛋白的纳米激动剂，其结合了锰 (II) 离子和 β-拉帕醌，可协同激活树突状细胞 (DC) 中的 cGAS-STING 信号传导，从而引发强大的适应性抗肿瘤免疫。Mn ²⁺锚定的甘露糖修饰的 BSA 和 β-拉帕醌负载的铁蛋白交联以提供生物反应性蛋白质纳米组装体，其在酸性血管周围肿瘤微环境 (TME) 中解离成单分散的蛋白质单元，从而增强肿瘤渗透和时空控制的 Mn ²⁺和 β-拉帕醌分别递送至 DC 和肿瘤细胞。β-lapachone 引起免疫原性肿瘤细胞凋亡并将大量 dsDNA 释放到 TME 中，而 Mn ²⁺增强 cGAS 对 dsDNA 的敏感性并增强 STING 信号以触发下游免疫刺激信号。cGAS-STING 纳米激动剂增强了肿瘤特异性 T 细胞介导的针对体内免疫原性差的实体瘤的免疫反应，为临床免疫治疗提供了一种强有力的方法。