NOTCH1, NOTCH2, NOTCH3 and NOTCH4 are transmembrane receptors that transduce juxtacrine signals of the delta‑like canonical Notch
ligand (DLL)1, DLL3, DLL4, jagged canonical Notch
ligand (JAG)1 and JAG2. Canonical Notch signaling activates the transcription of BMI1 proto‑oncogene polycomb ring finger,
cyclin D1, CD44,
cyclin dependent kinase inhibitor 1A, hes family
bHLH transcription factor 1, hes related family
bHLH transcription factor with YRPW motif 1, MYC, NOTCH3, RE1 silencing
transcription factor and
transcription factor 7 in a cellular context‑dependent manner, while non‑canonical Notch signaling activates NF‑κB and Rac family
small GTPase 1. Notch signaling is aberrantly activated in
breast cancer, non‑small‑cell
lung cancer and
hematological malignancies, such as T‑cell
acute lymphoblastic leukemia and diffuse large B‑cell
lymphoma. However, Notch signaling is inactivated in small‑cell
lung cancer and
squamous cell carcinomas. Loss‑of‑function NOTCH1 mutations are early events during esophageal
tumorigenesis, whereas gain‑of‑function NOTCH1 mutations are late events during T‑cell leukemogenesis and B‑cell lymphomagenesis. Notch signaling cascades crosstalk with
fibroblast growth factor and WNT signaling cascades in the tumor microenvironment to maintain cancer stem cells and remodel the tumor microenvironment. The Notch signaling network exerts oncogenic and tumor‑suppressive effects in a
cancer stage‑ or (sub)type‑dependent manner. Small‑molecule γ‑secretase inhibitors (AL101, MRK‑560,
nirogacestat and others) and antibody‑based biologics targeting Notch
ligands or receptors [ABT‑165, AMG 119,
rovalpituzumab tesirine (Rova‑T) and others] have been developed as
investigational drugs. The DLL3‑targeting antibody‑drug conjugate (ADC) Rova‑T, and DLL3‑targeting chimeric
antigen receptor‑modified T cells (CAR‑Ts), AMG 119, are promising anti‑cancer
therapeutics, as are other ADCs or CAR‑Ts targeting
tumor necrosis factor receptor superfamily member 17, CD19, CD22, CD30, CD79B, CD205,
Claudin 18.2,
fibroblast growth factor receptor (FGFR)2, FGFR3, receptor‑type tyrosine‑protein
kinase FLT3, HER2,
hepatocyte growth factor receptor, NECTIN4, inactive tyrosine‑protein
kinase 7, inactive tyrosine‑protein
kinase transmembrane receptor ROR1 and tumor‑associated
calcium signal transducer 2. ADCs and CAR‑Ts could alter the therapeutic framework for refractory
cancers, especially diffuse‑type
gastric cancer,
ovarian cancer and
pancreatic cancer with peritoneal dissemination. Phase III clinical trials of Rova‑T for patients with small‑cell
lung cancer and a phase III clinical trial of
nirogacestat for patients with
desmoid tumors are ongoing. Integration of human intelligence, cognitive computing and explainable artificial intelligence is necessary to construct a Notch‑related knowledge‑base and optimize Notch‑targeted
therapy for patients with
cancer.