中文摘要：
环状GMP–AMP合酶（cGAS）–干扰素基因刺激因子（STING）通路是先天免疫的核心调控因子，也是癌症免疫治疗的有前景的靶点。然而，STING激动剂的临床转化受到响应率不理想和剂量毒性（尤其是在肝脏）影响的限制。这些挑战凸显了STING信号存在内源性抑制因子，并强调需要开发能够实现组织特异性调控STING活性的策略。在此，我们鉴定了前蛋白转化酶枯草溶菌素/酵母Kexin型9（PCSK9），这是胆固醇代谢的关键调节因子，作为STING激活的负调节因子。在机制上，PCSK9与STING竞争结合共享的货物受体，而该受体对STING的转运至关重要。PCSK9缺失显著增强了STING激动剂的免疫刺激效应。利用肝脏中PCSK9表达相对于肿瘤高的特点，我们开发了一种配方，将低剂量STING激动剂与针对PCSK9的siRNA一同递送，从而实现肿瘤选择性的STING激活，同时将肝毒性降低。这些发现揭示了PCSK9在先天免疫调节中出乎意料的作用，并建立了一种增强基于STING的免疫疗法安全性和有效性的治疗方法，同时对其他STING相关疗法（包括放疗和化疗）具有更广泛的应用意义。
英文摘要：
The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway is a central regulator of innate immunity and a promising target for cancer immunotherapy. However, the clinical translation of STING agonists is limited by suboptimal response rates and dose-limiting toxicities, particularly in the liver. These challenges highlight the presence of endogenous inhibitors of STING signaling and underscore the need for strategies that enable tissue-specific modulation of STING activity. Here, we identify proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism, as a negative modulator of STING activation. Mechanistically, PCSK9 competes with STING for binding to a shared cargo receptor, which is critical for STING trafficking. PCSK9 deficiency markedly enhances the immunostimulatory effects of STING agonists. Capitalizing on the elevated expression of PCSK9 in the liver relative to tumors, we develop a formulation that delivers a low-dose STING agonist alongside PCSK9-targeting siRNA, thereby achieving tumor-selective STING activation while minimizing hepatotoxicity. These findings reveal an unanticipated role for PCSK9 in innate immune regulation and establish a therapeutic approach to enhance the safety and efficacy of STING-based immunotherapies, with broader implications for other STING-associated modalities, including radiotherapy and chemotherapy.
论文信息：
论文题目：Silencing PCSK9 reshapes the spatiotemporal activation of STING for safe and effective cancer immunotherapy
期刊名称：Nature Communications
时间期卷：16, Article number: 11622(2025)
在线时间：2025年11月25日
DOI：10.1038/s41467-025-66630-x
产品信息：
货号：C-005
规格：5ml
品牌：Liposoma
产地：荷兰
名称：Clodronate Liposomes氯膦酸盐脂质体
办事处：靶点科技
Clodronate Liposomes氯膦酸盐脂质体在小鼠结肠癌细胞系MC38结肠癌模型清除巨噬细胞。荷兰Liposoma巨噬细胞清除剂ClodronateLiposomes见刊于Nature Communications：沉默 PCSK9 重塑 STING 的时空激活，以实现安全有效的癌症免疫治疗。
Liposoma巨噬细胞清除剂Clodronate Liposomes氯膦酸二钠脂质体清除巨噬细胞的材料和方法：
To investigate which population of immune cells contributed to the therapeutic efficacy of NPsiPCSK9/cGAMP, 200 µg/dose anti-mouse CD4 (GK1.5, Selleck, Cat# A2101), anti-mouse CD8α (2.43, Selleck, Cat# A2102), anti-mouse NK1.1 (PK136, Selleck, Cat# A2114) and clodronate liposomes (LIPOSOMA, Cat# C-005) were intraperitoneally injected into MC38 tumor-bearing mice on day-1, 1, 3, 5, 7 post the first injection of NPsiPCSK9/cGAMP (2 injections in total at 3-day intervals) to specifically deplete endogenous CD4+ T cells, CD8+ T cells, NK cells, and macrophages, respectively. Batf3−/− mice were used to test the contribution of cDC1s in the therapeutic effect of NPsiPCSK9/cGAMP. Rat IgG2b (LTF-2, Selleck, Cat# A2116) was used as the isotype control for those in vivo depleting antibodies.
材料和方法文献截图：
