The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. 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. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.

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Kristen rat sarcoma (KRAS) gene is one of the most common mutated oncogenes in solid tumors. Yet, KRAS inhibitors did not follow suit with the development of targeted therapy, for the structure of KRAS has been considered as being implausible to target for decades. Chemotherapy was the initial recommended therapy for KRAS-mutant cancer patients, which was then replaced by or combined with immunotherapy. KRAS G12C inhibitors became the most recent breakthrough in targeted therapy, with Sotorasib being approved by the Food and Drug Administration (FDA) based on its significant efficacy in multiple clinical studies. However, the subtypes of the KRAS mutations are complex, and the development of inhibitors targeting non-G12C subtypes is still at a relatively early stage. In addition, the monotherapy of KRAS inhibitors has accumulated possible resistance, acquiring the exploration of combination therapies or next-generation KRAS inhibitors. Thus, other non-target, conventional therapies have also been considered as being promising. Here in this review, we went through the characteristics of KRAS mutations in cancer patients, and the prognostic effect that it poses on different therapies and advanced therapeutic strategy, as well as cutting-edge research on the mechanisms of drug resistance, tumor development, and the immune microenvironment.