刺
免疫系统
癌症免疫疗法
癌症研究
肿瘤微环境
干扰素基因刺激剂
免疫疗法
效应器
癌症
免疫检查点
免疫学
抗原
结直肠癌
生物
医学
先天免疫系统
遗传学
工程类
航空航天工程
作者
Larsen Vornholz,Sophie E. Isay,Zsuzsanna Kurgyis,Daniel C. Strobl,Patricia Loll,Mohammed H. Mosa,Malte D. Luecken,Michael Sterr,Heiko Lickert,Christof Winter,Florian R. Greten,Henner F. Farin,Fabian J. Theis,Jürgen Ruland
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2023-03-17
卷期号:9 (11)
被引量:1
标识
DOI:10.1126/sciadv.add8564
摘要
Immune checkpoint inhibitors (ICIs) enhance anticancer immunity by releasing repressive signals into tumor microenvironments (TMEs). To be effective, ICIs require preexisting immunologically "hot" niches for tumor antigen presentation and lymphocyte recruitment. How the mutational landscape of cancer cells shapes these immunological niches remains poorly defined. We found in human and murine colorectal cancer (CRC) models that the superior antitumor immune response of mismatch repair (MMR)-deficient CRC required tumor cell-intrinsic activation of cGAS-STING signaling triggered by genomic instability. Subsequently, we synthetically enforced STING signaling in CRC cells with intact MMR signaling using constitutively active STING variants. Even in MMR-proficient CRC, genetically encoded gain-of-function STING was sufficient to induce cancer cell-intrinsic interferon signaling, local activation of antigen-presenting cells, recruitment of effector lymphocytes, and sensitization of previously "cold" TMEs to ICI therapy in vivo. Thus, our results introduce a rational strategy for modulating cancer cell-intrinsic programs via engineered STING enforcement to sensitize resistant tumors to ICI responsiveness.
科研通智能强力驱动
Strongly Powered by AbleSci AI