Ms4a4a, a member of the membrane-spanning 4-domains subfamily A, is a plasma membrane tetraspan molecule selectively expressed by macrophage-lineage cells [2]. It is induced during monocyte-to-macrophage differentiation, especially in the presence of interleukin 4 or dexamethasone [2]. MS4A4A is involved in multiple pathways such as the PI3K/AKT and JAK/STAT6 pathways [1]. It plays a significant role in immunity, macrophage polarization, and is associated with various disease conditions [1,2,3]. Genetic models, like gene knockout (KO) mouse models, are valuable for studying its functions.

In experimental models of tumor progression and metastasis, Ms4a4a-deficient macrophages showed defective dectin-1-mediated activation and NK cell-mediated metastasis control, indicating its importance in this process [2]. In murine subcutaneous and orthotopic transplanted tumor models, in vivo inhibition of MS4A4A and anti-MS4A4A monoclonal antibody treatment curbed tumor growth, improved the effect of immune checkpoint inhibitor (ICI) therapy, and reshaped the tumor immune microenvironment by reducing M2-TAM and exhausted T-cell infiltration while increasing effector CD8+ T-cell infiltration [1]. In glioblastoma in vivo models, inhibiting MS4A4A and combining immune checkpoint blockade (ICB) therapy effectively inhibited tumor growth, reshaped the tumor immune microenvironment, and led to complete tumor eradication [3].

In conclusion, Ms4a4a is crucial for macrophage differentiation, polarization, and immune-related functions. KO mouse models have revealed its role in cancer, especially in regulating the tumor immune microenvironment and enhancing immunotherapy efficacy. These findings suggest that targeting Ms4a4a could be a potential strategy for treating certain cancers, offering new insights into immunotherapeutic approaches [1,2,3].