Notch signaling in the tumor immune microenvironment of colorectal cancer: mechanisms and therapeutic opportunities

Abstract

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.

Keywords: CRC; GSIs; Immune; Notch signaling; Prognosis.

Fig. 1

Overview of the Notch Signaling Pathway and Its Role in Immune Cell Differentiation and Function. Upon binding of the Delta-like ligand (DLL) from an adjacent cell, the Notch receptor undergoes sequential cleavages first by ADAM10 and subsequently by γ-secretase, resulting in the release of the Notch intracellular domain (NICD). NICD translocates to the nucleus, where it engages transcriptional regulators such as CSL and MAML, initiating the transcription of target genes. Within hematopoiesis, Notch signaling is essential for directing hematopoietic stem cells (HSCs) toward specific immune lineages, influencing the differentiation and maturation of T cells, B cells, and myeloid cells (including monocytes, dendritic cells, and granulocytes). Through its role in guiding immune cell fate and function, Notch signaling is vital for maintaining immune homeostasis and supporting effective immune responses

Fig. 2

Regulatory Mechanisms of Dysregulated Notch Signaling in the CRC Immune Microenvironment. Abnormal activation of Notch signaling within the CRC microenvironment impacts various immune cell populations, especially regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). Dysregulated Notch signaling activates downstream pathways, notably PI3K/Akt, Wnt/β-catenin, and TGF-β2, which collectively establish an immunosuppressive tumor microenvironment. These pathways facilitate immune evasion by upregulating PD-L1 and cytokines that recruit tumor-promoting macrophages, while concurrently suppressing the activity of CD8 + T cells

Fig. 3

Clinical Significance of Notch Signaling in CRC: Prognostic and Therapeutic Potential. Aberrant Notch pathway activation drives transcriptional changes that support key oncogenic processes, which correlate with adverse clinicopathological features, including increased tumor size, advanced tumor stage, and metastasis to lymph nodes and the liver. Elevated Notch pathway activity is also associated with poorer overall survival in patients with CRC, underscoring its prognostic relevance in CRC management. Therapeutically, inhibiting the Notch pathway with γ-secretase inhibitors (GSIs) and monoclonal antibodies (mAbs) is under active investigation, with some agents demonstrating enhanced efficacy when combined with other CRC treatments