As immunotherapy has revolutionized cancer treatment, NOTCH signaling and its relation with antitumor immunity have attracted the attention of scientists. Recent studies indicate that the NOTCH pathway is far more extensive and complicated than previously believed. In the past two decades, various drugs targeting NOTCH signaling have been tested in preclinical and clinical settings, yet no drug has been approved. NOTCH signaling participates in various biological processes across species, such as organ formation, tissue function, and tissue repair thus, aberrant NOTCH signaling may cause pathological consequences. Generally, NOTCH is considered an ancient and highly conserved signaling pathway. NOTCH variants were also found in ancient humans and were found to be involved in brain size control 8.

Homologs of NOTCH were then identified in multiple metazoans, and all these NOTCH homologs shared similar structures and signaling components 4– 7. The NOTCH gene was first named in studies of Drosophila melanogaster with notched wings in the 1910s 1– 3. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations.

In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. The NOTCH gene was identified approximately 110 years ago.

Star stable codes that work 2017