Hes1 in malignant tumors: from molecular mechanism to therapeutic potential

Abstract

The occurrence and development of malignant tumors involve abnormalities in complex molecular regulatory networks, among which the abnormal activation of the transcriptional regulator hairy and enhancer of split 1 (Hes1) has attracted significant attention in recent years and is closely associated with prognosis in various malignancies. Hes1 exhibits high expression in various solid tumors and hematological malignancies, where it participates in alterations involving diverse immune cells, inflammatory factors, and the immune microenvironment, thereby promoting tumor cell proliferation, invasion, metastasis, and resistance to treatment. Recent studies have widely investigated the potential of targeting Hes1 and inhibiting its expression as a cancer therapeutic strategy, although its precise mechanisms of action are not yet fully elucidated. Hes1 interacts with critical pathways including Notch, JAK/STAT, PI3K/AKT/mTOR, and Wnt/β-catenin. These interactions form complex crosstalk networks that drive malignant transformation and progression. Furthermore, Hes1 plays a central role in the formation of an immunosuppressive tumor microenvironment (TME) and immune escape by regulating the expression of immune checkpoint-associated proteins, extracellular matrix (ECM) remodeling, and other processes, making it a highly promising therapeutic target. Notably, the expression level of Hes1 is significantly correlated with tumor clinical stage, prognosis, and drug resistance. This review comprehensively introduces the mechanisms of Hes1 in the progression of malignant tumors, with a particular focus on discussing its application and underlying mechanisms in tumor immunotherapy. It integrates the latest clinical evidence and preclinical research perspectives. The goal is to highlight the translational potential of Hes1 as a novel biomarker and molecular target.

Keywords: Hes1; malignant tumors; signal transduction; therapeutic targets; tumor microenvironment.

Figure 1

Schematic of Hes1 protein with its domains and corresponding functions. The Hes1 protein consists of three conserved domains: the bHLH domain, the Orange domain, and the WRPW motif. The bHLH domain, located at the N-terminus, comprises the Basic (b) region and the Helix-loop-helix (HLH) region. The Basic region mediates DNA binding, while the HLH region is involved in dimerization. The Orange domain specifically selects binding partners and recruits co-repressors. The WRPW motif, located at the C-terminus, enhances transcriptional repressive activity by binding to co-repressors.

Figure 2

Dual repressor functions of Hes1: active repression and passive repression. Active repression process: (A, B) Hes1 forms homodimers or heterodimers with itself or other bHLH factors such as Hey at the N-box or C-type sites of target gene promoters. It initiates active repression through interaction with corepressors, such as TLE/Groucho homologs. Passive repression process: (C, D) Hes1 can bind to bHLH activators (e.g., Mash1 and E47), inhibiting their ability to bind to the E-box of target genes, thereby triggering passive repression.

Figure 3

(Left) Notch pathway:  Notch ligands (e.g., Delta/Jagged) on adjacent cells bind to receptors on the target cell membrane. Cleavage by ADAM proteases and γ-secretase releases NICD, which translocates to the nucleus, binds CSL with co-activators (e.g., MAML), and initiates transcription of hes1.  (Right) Other pathways: - Wnt: Binds Frizzled/LRP5/6 to activate β-catenin nuclear translocation and hes1 transcription via Tcf/Lef; - Hedgehog (Hh): Binds Ptch to release Smo inhibition, activating Gli for direct hes1 promoter binding; - FGF2: Recruits ATF2 to the Hes1 promoter; - NGF: Binds p75NTR to upregulate Hes1  via NF-κB; - EGF: Modulates  Hes1 through ERK/AKT cascades.

Figure 4

Hes1-Mediated Immunosuppressive Network in the Tumor Microenvironment. (A) Immune checkpoint induction: Hes1 upregulates PD-1, CTLA-4, TIM-3, and LAG-3 to suppress T-cell activity. (B) Immunosuppressive cell expansion: Hes1 recruits immunosuppressive cells (MDSCs/Tregs) to amplify inhibition. (C) Induction of macrophage polarization: Hes1 polarizes TAMs toward M2 phenotype. (D) Cancer stem cell (CSC) activation: Hes1 activated via IL-6/IL-8 signaling drives CD133⁺/CD44⁺ cancer stem cell expansion and induces immune suppression. "Created with BioGDP.com" (Note: This platform was used for data visualization and is acknowledged in the Acknowledgments section.)