DLL4 (Delta Like Canonical Notch Ligand 4)

These findings identify IXN as a promising dual-targeting agent that inhibits both HIF-1α and DLL4 and demonstrate its potential to enhance immune checkpoint blockade. Simultaneous targeting of hypoxia-driven and VEGF-DLL4-mediated angiogenic pathways represents a compelling therapeutic strategy to overcome the limitations of current anti-angiogenic and immunotherapeutic approaches.

Our findings suggest that HIF-1α promotes radiotherapy resistance in HNSCC by activating the Notch1 signaling axis. Targeting this pathway may enhance radiosensitivity and provide a new strategy for overcoming hypoxia-driven resistance.

Blocking the DLL4-MCT4 axis stimulated anti-tumor immunity and synergized with anti-PD-1, improving response rates for first-line neoadjuvant therapy in TNBC. Our study revealed intrinsic mechanism by which TTN regulates the tumor immune microenvironment and provided a potential target for immunotherapy in TNBC with TTN inactivation.

Zou et al unravel that the adaptive ER stress response in bone marrow blood vessels restricts the post-transplant regeneration of immune progenitor cells by attenuating the expression of Notch ligand DLL4. Targeting ER stress sensor PERK can accelerate immune recovery after transplantation by enhancing DLL4-NOTCH3 signaling and IL7 cytokine production.

DLL4 expression in gastric cancer patients may predict poor prognosis and survival. Furthermore, the current data demonstrate the potential of Nanobody for detecting DLL4, and it may lead to develop novel therapies and diagnostics for tumors.

GPR81 supports breast cancer aggressiveness, and in MCF-7 cells, this occurs at least in part via DLL4. Our findings reveal a new GPR81-driven mechanism in breast cancer and substantiate GPR81 as a promising treatment target.

Finally, DLL4, a Notch ligand expressed in LECs, was identified as an upstream inducer of the Notch3-WNT5B axis in melanoma. This study elucidated WNT5B as a key molecular factor mediating bi-directional crosstalk between melanoma cells and lymphatic endothelium and promoting melanoma metastasis.

After Dll4 knockdown, the level of desma and Tnnt2c gene expression was significantly up-regulated. Tryptanthrin can inhibit tumor growth in vivo in a concentration-dependent manner by down-regulating Dll4 protein expression, and at the same time up-regulating the level of desma and Tnnt2c gene expression.

Our in vivo study confirmed the establishment of a bevacizumab-resistant human colorectal cancer model and further demonstrated that the addition of anti-ESM1 monoclonal antibodies to bevacizumab treatment significantly improved tumor response while downregulating DLL4 and MMP9. In conclusion, our study suggests that anti-hESM1 monoclonal antibodies have the potential to alleviate or overcome bevacizumab resistance, thereby providing new strategies and drug candidates for clinical research in the treatment of bevacizumab-resistant colorectal cancer.

These findings identify splenic B cell follicles and not the MZ as a central hub for stroma-driven Dll1/Notch2 signaling, with Notch empowering subsequent B cell migration and positioning to the MZ through a Myc-independent transcriptional program. As many Notch-regulated transcriptional targets are conserved in human Notch-driven B cell lymphomas, we speculate that principles of stroma-driven Notch signaling and its downstream effects in B cells have been conserved during evolution from mouse to human B cells – with the Notch signature tagging the B cell subsets that rely on conserved Notch programs and the B cell malignancies that hijack them.

We also discussed the challenges, limitations, and emerging research areas in targeting Dll4-expressing macrophages and provide an outlook on potential therapeutic strategies for the treatment of these diseases. By addressing the previously existing research gap, we've provided a roadmap that brings together fragmented insights, paving the way for more holistic research and potentially more effective therapeutic strategies centered on Dll4-expressing macrophages.

NOTCH pathway genes appear to play an important role in the progression of OC by regulating immune cells, endocrine resistance, Th1 and Th2 cell differentiation, and oxidative phosphorylation. JAG2 and NOTCH1 are potential biomarkers and therapeutic targets for the treatment of OC.