Slit2 is a secreted polypeptide that functions in cell migration regulation. It binds to Roundabout (Robo) receptors, activating intracellular signal transduction pathways. The Slit2-Robo signaling pathway is involved in various biological processes, such as axon guidance during central nervous system development, and has implications in immune response, vascular permeability, and angiogenesis [4].

In cancer, Slit2 shows a context-dependent role. In breast and lung cancer mouse models, endothelial-derived Slit2 promotes cancer cell migration and intravasation, as deletion of endothelial Slit2 suppresses metastatic dissemination. Conversely, deletion of tumoural Slit2 enhances metastatic progression, suggesting that cancer cells can co-opt innate RNA sensing to induce a chemotactic signalling pathway in endothelium via the TLR3-SLIT2 axis [1]. In glioblastoma, knockdown of SLIT2 in mouse glioma cells and patient-derived xenografts reduces tumor growth and makes tumors sensitive to immunotherapy, as SLIT2 promotes microglia/macrophage chemotaxis and tumor-supportive polarization via ROBO1-and ROBO2-mediated PI3K-γ activation [2]. In Ewing sarcoma, EWS::FLI1 induces Slit2 expression, and silencing of Slit2 or its receptors Robo1 and Robo2 inhibits Ewing sarcoma growth [5]. In small-cell lung cancer, SLIT2 overexpression or ROBO1 deletion restricts tumor growth, as SLIT2 suppresses the TGF-β1/β-catenin signaling pathway in both tumor cells and macrophages [6]. In gastric cancer, exosomes from N2-polarized tumor-associated neutrophils transfer miR-4745-5p/3911 to downregulate SLIT2, promoting cancer metastasis, and adenovirus-mediated overexpression of SLIT2 reverses this effect [7]. In liver fibrosis, Slit2-Robo1 signaling promotes liver injury and fibrosis through activation of hepatic stellate cells, as Slit2-Tg mice are more vulnerable to CCl4-induced liver injury and fibrosis, while Robo1/2(+/-) mice are less affected [3].

In conclusion, Slit2 plays diverse and context-specific roles in various biological processes and diseases, especially in cancer and fibrosis. Gene knockout and knockdown models in mice have been crucial in revealing these functions, providing potential therapeutic targets for treating related diseases.