刺
免疫系统
癌症研究
细胞毒性
医学
肿瘤微环境
免疫疗法
癌症免疫疗法
免疫学
生物
体外
生物化学
工程类
航空航天工程
作者
Wei Liu,Mohamad‐Gabriel Alameh,June F. Yang,Jonathan R. Xu,Paulo J.C. Lin,Ying K. Tam,Drew Weissman,Jianxin You
标识
DOI:10.3390/ijms232314504
摘要
Treating immunosuppressive tumors represents a major challenge in cancer therapies. Activation of STING signaling has shown remarkable potential to invigorate the immunologically "cold" tumor microenvironment (TME). However, we have shown that STING is silenced in many human cancers, including pancreatic ductal adenocarcinoma (PDAC) and Merkel cell carcinoma (MCC). In this study, we demonstrated that mRNA-lipid nanoparticle (LNP) technology could be used to efficiently deliver naturally occurring constitutively active STING mutant STINGR284S into these cancer cells to reactivate STING antitumor immunity and trigger robust killing of tumor cells. STING agonists are being actively pursued as cancer immunotherapies. However, traditional STING agonists can induce T cell cytotoxicity, counteracting the desired antitumor immune response. In addition, the antitumor efficacy of traditional STING agonists obligatorily depends on STING expression and does not work in STING-silenced cancers. Importantly, we found that STINGR284S mRNA-LNP does not introduce T cell cytotoxicity. Our studies demonstrated that mRNA-LNP delivery of STINGR284S can reactivate the antitumor response without introducing antiproliferative effects in lymphocytic immune cells, overcoming the toxicity and limitations of conventional STING agonists. Our work therefore identifies a novel therapeutic tool for reactivating antitumor immunity in an array of STING-silenced immunologically "cold" tumors that are refractory to current therapies.
科研通智能强力驱动
Strongly Powered by AbleSci AI