PDF(Pubmed)
Abstract：
Dysregulation of the Notch signaling pathway, which is highly conserved across species, can drive aberrant epigenetic modification, transcription, and translation. Defective gene regulation caused by dysregulated Notch signaling often affects networks controlling oncogenesis and tumor progression. Meanwhile, Notch signaling can modulate immune cells involved in anti- or pro-tumor responses and tumor immunogenicity. A comprehensive understanding of these processes can help with designing new drugs that target Notch signaling, thereby enhancing the effects of cancer immunotherapy. Here, we provide an up-to-date and comprehensive overview of how Notch signaling intrinsically regulates immune cells and how alterations in Notch signaling in tumor cells or stromal cells extrinsically regulate immune responses in the tumor microenvironment (TME). We also discuss the potential role of Notch signaling in tumor immunity mediated by gut microbiota. Finally, we propose strategies for targeting Notch signaling in cancer immunotherapy. These include oncolytic virotherapy combined with inhibition of Notch signaling, nanoparticles (NPs) loaded with Notch signaling regulators to specifically target tumor-associated macrophages (TAMs) to repolarize their functions and remodel the TME, combining specific and efficient inhibitors or activators of Notch signaling with immune checkpoint blockers (ICBs) for synergistic anti-tumor therapy, and implementing a customized and effective synNotch circuit system to enhance safety of chimeric antigen receptor (CAR) immune cells. Collectively, this review aims to summarize how Notch signaling intrinsically and extrinsically shapes immune responses to improve immunotherapy.
摘要：
Notch信号通路的失调,在物种中高度保守，可以驱动异常的表观遗传修饰，转录,和翻译。由Notch信号传导失调引起的缺陷基因调节通常影响控制肿瘤发生和肿瘤进展的网络。同时,Notch信号传导可以调节参与抗肿瘤或前肿瘤应答和肿瘤免疫原性的免疫细胞。对这些过程的全面了解可以帮助设计靶向Notch信号的新药。从而增强癌症免疫治疗的效果。这里,我们提供了关于Notch信号如何内在调节免疫细胞以及肿瘤细胞或基质细胞中Notch信号的改变如何外在调节肿瘤微环境(TME)中的免疫应答的最新和全面概述.我们还讨论了Notch信号在肠道微生物群介导的肿瘤免疫中的潜在作用。最后,我们提出了在癌症免疫治疗中靶向Notch信号的策略.这些包括溶瘤病毒疗法结合抑制Notch信号，负载有Notch信号调节子的纳米颗粒（NPs）特异性靶向肿瘤相关巨噬细胞（TAMs），以使它们的功能复极化并重塑TME，结合特异性和有效的Notch信号抑制剂或激活剂与免疫检查点阻断剂（ICBs）协同抗肿瘤治疗，并实施定制且有效的synNotch电路系统，以增强嵌合抗原受体（CAR）免疫细胞的安全性。总的来说，这篇综述旨在总结Notch信号内在和外在如何塑造免疫反应以改善免疫治疗。
