肺肿瘤中的促肿瘤巨噬细胞对免疫治疗提出了重大挑战。在这里，我们介绍了一种用于激活抗肿瘤巨噬细胞和树突状细胞的 pH 响应纳米医学方法。使用层状双氢氧化物纳米片载体，我们将 T 型钙通道抑制剂 (TTA-Q6) 和 CD47 抑制剂 (RRX-001) 共同递送到肺部肿瘤中。在肿瘤酸性环境中，TTA-Q6被释放，破坏癌细胞钙摄取，引起内质网应激并诱导钙网蛋白转移至细胞表面。表面钙网蛋白激活巨噬细胞并触发树突状细胞成熟，促进有效的抗原呈递，从而激活抗肿瘤 T 细胞。同时，RRX-001 降低 CD47 蛋白水平，有助于防止富含钙网蛋白的癌细胞免疫逃逸。在雄性小鼠的肺部肿瘤模型中，这种组合方法显示出抗肿瘤作用和针对肿瘤再次暴露的免疫力，突出了其肺癌免疫治疗的潜力。© 2023。作者。

Pro-tumoral macrophages in lung tumors present a significant challenge in immunotherapy. Here, we introduce a pH-responsive nanomedicine approach for activating anti-tumoral macrophages and dendritic cells. Using a layered double hydroxide nanosheet carrier, we co-deliver a T-type calcium channel inhibitor (TTA-Q6) and a CD47 inhibitor (RRX-001) into lung tumors. In the tumor acidic environment, TTA-Q6 is released, disrupting cancer cell calcium uptake, causing endoplasmic reticulum stress and inducing calreticulin transfer to the cell surface. Surface calreticulin activates macrophages and triggers dendritic cell maturation, promoting effective antigen presentation and therefore activating antitumor T cells. Simultaneously, RRX-001 reduces CD47 protein levels, aiding in preventing immune escape by calreticulin-rich cancer cells. In lung tumor models in male mice, this combined approach shows anti-tumor effects and immunity against tumor re-exposure, highlighting its potential for lung cancer immunotherapy.© 2023. The Author(s).