The Notch signaling pathway: a potential target for cancer immunotherapy

• Published in: Journal of hematology and oncology Vol. 16; no. 1; p. 45
• Main Authors: Li, Xinxin, Yan, Xianchun, Wang, Yufeng, Kaur, Balveen, Han, Hua, Yu, Jianhua
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 02.05.2023; BioMed Central; BMC
• Subjects: Angiogenesis; Antibodies; Antigens; Antigens, Neoplasm - pharmacology; Cancer; Cancer immunotherapy; Cancer therapies; Care and treatment; Cells; Chimeric antigen receptor (CAR); Chimeric antigen receptors; Clinical trials; Cytokines; Development and progression; Drug therapy; Epigenetic inheritance; Epigenetics; Gene regulation; Genetic aspects; Genetic transcription; Genetic translation; Hematology; Humans; Immune cells; Immune checkpoint; Immune response; Immunogenicity; Immunosuppressive agents; Immunotherapy; Intestinal microflora; Ligands; Liver cancer; Lung cancer; Lymphocytes; Macrophages; Nanoparticles; Neoplasms - pathology; Notch signaling; Oncology; Oncolysis; Pancreatic cancer; Patients; Proteins; Review; Signal Transduction; Stromal cells; Tumor cells; Tumor Microenvironment; Tumor-associated macrophages; Tumorigenesis; Tumors; Wildlife conservation; Chimeric antigen receptor (CAR); Immune checkpoint; Cancer immunotherapy; Immune cells; Notch signaling; Tumor-associated macrophages
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-023-01439-z

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.