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 been shown to play crucial roles in immune function, angiogenesis, and cell-cell interactions. Sema4a has 4 types of receptors: Plexin D family, Plexin B family, Tim-2, and Nrp-1 [3].

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, indicating its role in promoting cancer invasion through inducing Epithelial-mesenchymal transition (EMT) of PCa cells and establishing a positive loop with IL-10 in stromal cells [1].

In multiple sclerosis (MS), approximately one-third of patients with high Sema4a levels were unresponsive to IFN-β treatment. In an animal model of MS (EAE), administration of Sema4A concurrently with IFN-β abrogated the efficacy of IFN-β, as Sema4a promoted Th1 and Th17 differentiation and increased adhesive activation of T cells to endothelial cells [2,6]. In the effector phase of adoptively transferred EAE model, Sema4a-deficient (Sema4a KO) recipient mice receiving Th17-skewed WT myelin oligodendrocyte glycoprotein (MOG)-specific encephalitogenic T cells showed a reduced clinical score, suggesting Sema4a is involved in accelerating Th17-cell-mediated neuroinflammation in the effector phase [4].

In non-small cell lung cancer (NSCLC), Sema4a-positive tumors responded better to anti-programmed cell death 1 (PD-1) antibody. Sema4a promoted cytotoxicity and proliferation of tumor-specific CD8+ T cells in murine models, potentially being a biomarker for predicting and promoting ICI efficacy [5].

In conclusion, Sema4a plays essential roles in immune function, angiogenesis, and cancer progression. Studies using Sema4a KO mouse models have revealed its significance in prostate cancer invasion, MS pathogenesis, and the response to certain cancer immunotherapies. These findings contribute to a better understanding of the underlying mechanisms of these diseases and may provide potential therapeutic targets.