Sun Jiachun, Chen Yi, Xu Ziyi, Wang Weizheng, Li Penghui
Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, 471003, China.
Department of Children's gastroenterology, Anhui Children's Hospital, Hefei, Anhui, 230000, China.
J Transl Med. 2025 Mar 12;23(1):315. doi: 10.1186/s12967-025-06282-z.
Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, driven by a complex interplay of genetic, environmental, and immune-related factors. Among the pivotal pathways implicated in CRC tumorigenesis, the Notch signaling pathway is instrumental in governing cell fate decisions, tissue renewal, homeostasis, and immune cell development. As a highly conserved mechanism, Notch signaling not only modulates tumor cell behavior but also shapes the immune landscape within the tumor microenvironment (TME). Aberrant Notch signaling in CRC fosters immune evasion and tumor progression through its effects on the balance and functionality of immune cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Elevated Notch pathway activation correlates with advanced clinicopathological features and poorer clinical outcomes, highlighting its relevance as both a prognostic biomarker and a therapeutic target. Therapeutic approaches aimed at inhibiting the Notch pathway, such as γ-secretase inhibitors (GSIs) or monoclonal antibodies (mAbs) in combination with other therapies, have demonstrated promising efficacy in preclinical and clinical settings. This review examines the impact of Notch signaling on CRC immunity, elucidating its regulatory mechanisms within immune cells and its role in promoting tumor progression. Additionally, this review discusses therapeutic strategies targeting Notch signaling, including GSIs, mAbs, and potential combination therapies designed to overcome resistance and improve patient outcomes. By elucidating the multifaceted role of Notch within the CRC TME, this review underscores its potential as a target for innovative therapeutic strategies.
结直肠癌（CRC）仍然是全球癌症相关发病和死亡的主要原因，由遗传、环境和免疫相关因素的复杂相互作用驱动。在与CRC肿瘤发生相关的关键途径中，Notch信号通路在控制细胞命运决定、组织更新、内环境稳定和免疫细胞发育方面发挥着重要作用。作为一种高度保守的机制，Notch信号不仅调节肿瘤细胞行为，还塑造肿瘤微环境（TME）中的免疫格局。CRC中异常的Notch信号通过影响免疫细胞（包括髓源性抑制细胞（MDSCs）和肿瘤相关巨噬细胞（TAMs））的平衡和功能，促进免疫逃逸和肿瘤进展。Notch通路激活升高与晚期临床病理特征和较差的临床结果相关，突出了其作为预后生物标志物和治疗靶点的相关性。旨在抑制Notch通路的治疗方法，如γ-分泌酶抑制剂（GSIs）或单克隆抗体（mAbs）与其他疗法联合使用，在临床前和临床环境中已显示出有前景的疗效。本综述探讨了Notch信号对CRC免疫的影响，阐明了其在免疫细胞内的调节机制及其在促进肿瘤进展中的作用。此外，本综述讨论了针对Notch信号的治疗策略，包括GSIs、mAbs以及旨在克服耐药性和改善患者预后的潜在联合疗法。通过阐明Notch在CRC TME中的多方面作用，本综述强调了其作为创新治疗策略靶点的潜力。
