Yang Lei, Li Zhen, Huang Xiaoxi, Huang Lei, Fu Yangkai, Zhao Baocheng, Zhang Yudong, Ma Liangang, Jing Shuai, Fu Liyuan, Zhang Dong, Qu Hao
Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongti South load, Chaoyang District, Beijing 100020, PR China.
Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongti South load, Chaoyang District, Beijing 100020, PR China; Department of Urology Surgery, Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongti South load, Chaoyang District, Beijing 100020, PR China.
J Control Release. 2025 Aug 10;384:113865. doi: 10.1016/j.jconrel.2025.113865. Epub 2025 May 22.
Advanced colorectal cancer (CRC) is characterized by a highly suppressive immune tumor microenvironment (TME) and is insensitive to immunotherapy. The induction of cancer immunogenic cell death (ICD) has been acknowledged as a promising immunotherapeutic strategy. Here, we demonstrate that the long noncoding RNA VPS9D1-AS1 is expressed predominantly in consensus molecular subtype (CMS)-2 CRC, and that its overexpression is associated with immune checkpoint blockade (ICB) sensitivity. A lipid-nanoparticle-(LNP)-based drug delivery system loaded with antisense oligonucleotides (ASOs) was established to target VPS9D1-AS1. This LNP-based drug exhibited high efficiency in inhibiting VPS9D1-AS1 expression in both tumor cells and patient-derived-xenograft (PDX) tumors, significantly suppressing tumor growth and metastasis. Mechanistically, targeting VPS9D1-AS1 activates MLKL-induced ICD, which in turn promotes antigen exposure in tumor cells. Moreover, VPS9D1-AS1 blockade inhibits HLA-G to sensitize CRC cells to immunotherapy. Consequently, LNP-based nano-ASO drugs targeting VPS9D1-AS1 promote TME remodeling by increasing the infiltrations of CD8 T cells and dendritic cells (DCs). In addition, targeting VPS9D1-AS1 harmonizes the crosstalk between tumor cells and DCs via the AXL/GAS6 pathway. In vivo animal studies demonstrated that the combined targeting of PD1 and VPS9D1-AS1 enhances the efficacy of ICB treatment. It is anticipated that nanodrugs targeting VPS9D1-AS1 can be applied in clinical advanced CRC therapy in the near future.
晚期结直肠癌（CRC）的特征是具有高度抑制性的免疫肿瘤微环境（TME），并且对免疫疗法不敏感。诱导癌症免疫原性细胞死亡（ICD）已被认为是一种有前景的免疫治疗策略。在此，我们证明长链非编码RNA VPS9D1-AS1主要在共识分子亚型（CMS）-2 CRC中表达，并且其过表达与免疫检查点阻断（ICB）敏感性相关。建立了一种基于脂质纳米颗粒（LNP）的载有反义寡核苷酸（ASO）的药物递送系统来靶向VPS9D1-AS1。这种基于LNP的药物在抑制肿瘤细胞和患者来源异种移植（PDX）肿瘤中VPS9D1-AS1表达方面表现出高效性，显著抑制肿瘤生长和转移。从机制上讲，靶向VPS9D1-AS1可激活MLKL诱导的ICD，进而促进肿瘤细胞中的抗原暴露。此外，VPS9D1-AS1阻断可抑制HLA-G，使CRC细胞对免疫疗法敏感。因此，靶向VPS9D1-AS1的基于LNP的纳米ASO药物通过增加CD8 T细胞和树突状细胞（DC）的浸润来促进TME重塑。此外，靶向VPS9D1-AS1通过AXL/GAS6途径协调肿瘤细胞与DC之间的串扰。体内动物研究表明，联合靶向PD1和VPS9D1-AS1可增强ICB治疗的疗效。预计靶向VPS9D1-AS1的纳米药物在不久的将来可应用于临床晚期CRC治疗。
