Fig. 2

Mechanisms by which Notch signaling regulates anti- or pro-tumor functions of immune cells. A. I: After stimulation with Jagged2, Dll1, or Dll4, Notch signaling promotes the differentiation of CD34⁺ precursors into NK cells and enhances the anti-tumor properties of the NK cells by potentiating the secretion of IFN-γ and GZMB; II: Dll1 or other ligands that activate Notch1 or Notch2 increase the expression of CD16, KIRs, IFNG, enhance the maturation and cytotoxicity of NK cells. B. I: In IL22⁺ ILCs, AhR ligand enhances the transcription of Notch1 and Notch2 by activating AhR, sustains the NKp46⁺ ILC population, and, in part, also sustains the LTi-like cell population by activating Notch signaling; II: In LTi cells, T-bet promotes the transcription of Notch1 and Notch2 and also promotes the transition of LTi cells into NKp46⁺ ILCs; III: In NKp46⁻ ILCs, Notch activation mediated by Notch2 signaling promote the transcription of T-bet, AhR, and RORγt through canonical Notch signaling, which is mediated by RBP-J. This promotes the transition of NKp46⁻ ILCs into NKp46⁺ ILCs. C. I: Activation of canonical Notch signaling by Dll1 promotes the transcription of Socs3 and miR-125a but inhibits the transcription of SIRPα, promoting M1 macrophage polarization and inhibiting M2 macrophage polarization; II: In the liver TME, myeloid cell-mediated canonical Notch signaling positively regulates the differentiation of moTAMs, but negatively regulates the proliferation of kclTAMs by regulating WNT − β-CATENIN signaling transmission in kclTAMs. D. I: In the glioma TME, oHSVs induce Jagged1 expression on macrophages; Jagged1-presenting macrophages spread activation of Notch signaling on TAMs, promotes the release of CCL2 from TAMs, recruits MDSCs, and then inhibits the cytotoxicity of CD8⁺ T cells; II: In MDSCs, activated NICD inhibits MCT2 expression, reduces the uptake of lactate from the TME, inhibits Cox2 transcription, promotes MDSCs transition into M1(tumor-suppressive)-TAMs. E. Activation of RBP-J-mediated Notch signaling in DCs promotes the transcription of APC-related genes, migration-related genes, and CCR2; this activation enhances antigen presentation by DCs to T cells and accelerates tumor lysis. Dll4 of DCs activates Notch receptor of T cells, promotes the transcription of a series of genes (GATA3, T-bet, RORC, IL-4, IFNG and IL-17) that promote the differentiation of T cells or directly enhances the T cells’ cytotoxicity. F. Notch1/2 activated by Dll ligand promotes the transcription of Gzmb, Ifng, and Pdcd1, and enhances the anti-tumor ability of T cells by releasing IFN-γ and GZMB. However, Notch signaling activation  also inhibits the anti-tumor property of T cells by increasing PD-1 expression. Transcriptional and immune response regulator (TCIM) inhibits Notch signaling, but enhancer of zeste homolog 2 (EZH2) activates Notch signaling by inhibiting the expression of Notch suppressors (Numb and Fbxw7). Figure was created with BioRender.com