Slit2 is a secreted polypeptide that was initially known for its role in regulating the migration of developing axons during central nervous system (CNS) development, acting through Roundabout (Robo) receptors to mediate intracellular signal transduction pathways [4]. It has since been found to be involved in various biological processes such as cell migration, immune response, vascular permeability, and angiogenesis [4].

In cancer, its role seems context-dependent. Deleting endothelial Slit2 suppressed metastatic dissemination in mouse models of breast and lung cancer, while deletion of tumoural Slit2 enhanced metastatic progression, suggesting that cancer cells co-opt innate RNA sensing to induce a chemotactic signalling pathway in endothelium via the TLR3-SLIT2 axis [1]. In gliomas, knockdown of SLIT2 in mouse glioma cells and patient-derived GBM xenografts reduced tumor growth and rendered tumors sensitive to immunotherapy [2]. In Ewing sarcoma, silencing of Slit2 strongly inhibited the growth of Ewing sarcoma cells [5]. Conversely, in small-cell lung cancer, SLIT2 overexpression restricted tumor growth in vitro and in vivo, and in gastric cancer, exosomal miR-4745-5p/3911 from N2-polarized tumor-associated neutrophils promoted metastasis by downregulating SLIT2 [6,7].

In liver fibrosis, Slit2-Robo1 signaling promoted liver injury and fibrosis through activation of hepatic stellate cells, as Slit2-Tg mice were more vulnerable to CCl4-induced liver injury and fibrosis while Robo1/2(+/-) mice had attenuated responses [3].

In conclusion, Slit2 plays diverse and context-specific roles in various biological processes and diseases. Gene knockout (KO) and conditional knockout (CKO) mouse models have been instrumental in revealing its role in cancer metastasis, glioma growth, liver fibrosis, among others. Understanding the functions of Slit2 provides potential therapeutic targets for these diseases.