沉默 PCSK9 重塑 STING 的時(shí)空激活，以實(shí)現(xiàn)安全有效的癌癥免疫治療

中文摘要：

環(huán)狀GMP–AMP合酶（cGAS）–干擾素基因刺激因子（STING）通路是先天免疫的核心調(diào)控因子，也是癌癥免疫治療的有前景的靶點(diǎn)。然而，STING激動(dòng)劑的臨床轉(zhuǎn)化受到響應(yīng)率不理想和劑量毒性（尤其是在肝臟）影響的限制。這些挑戰(zhàn)凸顯了STING信號(hào)存在內(nèi)源性抑制因子，并強(qiáng)調(diào)需要開發(fā)能夠?qū)崿F(xiàn)組織特異性調(diào)控STING活性的策略。在此，我們鑒定了前蛋白轉(zhuǎn)化酶枯草溶菌素/酵母Kexin型9（PCSK9），這是膽固醇代謝的關(guān)鍵調(diào)節(jié)因子，作為STING激活的負(fù)調(diào)節(jié)因子。在機(jī)制上，PCSK9與STING競(jìng)爭(zhēng)結(jié)合共享的貨物受體，而該受體對(duì)STING的轉(zhuǎn)運(yùn)至關(guān)重要。PCSK9缺失顯著增強(qiáng)了STING激動(dòng)劑的免疫刺激效應(yīng)。利用肝臟中PCSK9表達(dá)相對(duì)于腫瘤高的特點(diǎn)，我們開發(fā)了一種配方，將低劑量STING激動(dòng)劑與針對(duì)PCSK9的siRNA一同遞送，從而實(shí)現(xiàn)腫瘤選擇性的STING激活，同時(shí)將肝毒性降低。這些發(fā)現(xiàn)揭示了PCSK9在先天免疫調(diào)節(jié)中出乎意料的作用，并建立了一種增強(qiáng)基于STING的免疫療法安全性和有效性的治療方法，同時(shí)對(duì)其他STING相關(guān)療法（包括放療和化療）具有更廣泛的應(yīng)用意義。

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.

論文信息：

論文題目：Silencing PCSK9 reshapes the spatiotemporal activation of STING for safe and effective cancer immunotherapy

期刊名稱：Nature Communications

時(shí)間期卷：16, Article number: 11622(2025)

在線時(shí)間：2025年11月25日

DOI：10.1038/s41467-025-66630-x

產(chǎn)品信息：

貨號(hào)：C-005

規(guī)格：5ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱：Clodronate Liposomes氯膦酸鹽脂質(zhì)體

辦事處：靶點(diǎn)科技

Clodronate Liposomes氯膦酸鹽脂質(zhì)體在小鼠結(jié)腸癌細(xì)胞系MC38結(jié)腸癌模型清除巨噬細(xì)胞。荷蘭Liposoma巨噬細(xì)胞清除劑ClodronateLiposomes見刊于Nature Communications：沉默 PCSK9 重塑 STING 的時(shí)空激活，以實(shí)現(xiàn)安全有效的癌癥免疫治療。

Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes氯膦酸二鈉脂質(zhì)體清除巨噬細(xì)胞的材料和方法：

In vivo cell depletion

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.

材料和方法文獻(xiàn)截圖：