Sema4a, a member of the semaphorin family, was initially recognized as an axon guidance factor in the nervous system. It is preferentially expressed on immune cells and has four types of receptors: Plexin D family, Plexin B family, Tim-2, and Nrp-1. Sema4a plays critical roles in cell-cell interactions, immune-cell activation, differentiation, migration, angiogenesis, and is also associated with carcinogenesis and retinal systems [4].

In prostate cancer, Sema4A was highly expressed in tissues, correlated with Gleason scores and distant metastasis. Genetic depletion of Sema4A prevented lung metastasis in PCa xenograft models, suggesting its crucial role in promoting invasion through establishing a positive loop with IL-10 in stromal cells and inducing Epithelial-mesenchymal transition (EMT) of PCa cells [1].

In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), Sema4A-deficient (Sema4A KO) recipient mice receiving Th17-skewed WT myelin oligodendrocyte glycoprotein-specific encephalitogenic T cells showed reduced clinical scores. MS patients with high Sema4A levels had more severe disabilities, earlier disease onset, and were unresponsive to IFN-β treatment [2,3,5].

In non-small cell lung cancer, Sema4A-positive tumors responded better to anti-programmed cell death 1 (PD-1) antibody, and Sema4A promoted cytotoxicity and proliferation of tumor-specific CD8+ T cells in murine models [6].

In conclusion, Sema4a is involved in multiple biological processes and diseases. Gene knockout models, especially in the context of prostate cancer, multiple sclerosis, and non-small cell lung cancer, have revealed its role in promoting cancer invasion, accelerating neuroinflammation, and influencing the efficacy of immunotherapy. These findings contribute to understanding the biological functions of Sema4a and provide potential therapeutic targets for related diseases.