Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, China.
Experiment & Teaching Center, School of Pharmacy, Fudan University, Shanghai 201203, China.
Int Immunopharmacol. 2024 Dec 5;142(Pt A):113111. doi: 10.1016/j.intimp.2024.113111. Epub 2024 Sep 9.
The massive infiltration of suppressor immune cells within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is a major cause of treatment resistance. Reducing this infiltration may represent a potentially effective therapeutic strategy. Sphingomyelin synthase 2 (SMS2) is a crucial enzyme for sphingomyelin synthesis, contributing significantly to the integrity and function of the plasma membrane. In this study, we developed a self-assembling SMS2 siRNA gene expression plasmid for in vivo delivery. The SMS2 siRNA specifically inhibits SMS2 expression while preserving the expression and activity of SMS1. Administration of the self-assembling SMS2 siRNA suppresses tumor growth in a murine model of Panc02 pancreatic carcinoma, modulates the polarization of tumor-associated macrophages (TAMs), and reduces the infiltration of tumor-associated neutrophils (TANs) by regulating the NF-κB/CXCL5 pathway. Consequently, utilizing SMS2 siRNA to improve the local immunosuppressive microenvironment holds promise for pancreatic cancer therapy.
肿瘤微环境（TME）中抑制性免疫细胞的大量浸润是胰腺导管腺癌（PDAC）治疗耐药的主要原因。减少这种浸润可能代表一种潜在有效的治疗策略。鞘氨醇合酶 2（SMS2）是鞘氨醇合成的关键酶，对质膜的完整性和功能有重要贡献。在这项研究中，我们开发了一种用于体内递送的自组装 SMS2 siRNA 基因表达质粒。SMS2 siRNA 特异性抑制 SMS2 的表达，同时保留 SMS1 的表达和活性。自组装 SMS2 siRNA 的给药抑制了 Panc02 胰腺癌细胞小鼠模型中的肿瘤生长，通过调节 NF-κB/CXCL5 通路调节肿瘤相关巨噬细胞（TAMs）的极化，并减少肿瘤相关中性粒细胞（TANs）的浸润。因此，利用 SMS2 siRNA 改善局部免疫抑制微环境有望成为胰腺癌治疗的一种方法。
