EBI3 (Epstein-Barr virus induced 3) is a β-subunit cytokine that functions primarily as a component of heterodimeric IL-12 family cytokines with pleiotropic immune effects 1. EBI3 canonically associates with α-subunits (p19, p28, p35) to form IL-39, IL-27, and IL-35 respectively, regulating T helper cell differentiation, B cell isotype switching, and innate immune responses 2. Mechanistically, EBI3 exhibits dual functionality: it acts as a chaperone-like protein promoting proper protein folding in collaboration with calnexin under inflammatory conditions 2, and secreted partnerless EBI3 can bind extracellular cytokines including IFN-γ and IL-10, functioning as a cytokine sink that abrogates their signaling 3. In disease contexts, EBI3 plays contradictory roles. While IL-35 (EBI3-p35 heterodimer) and EBI3 alone demonstrate anti-inflammatory properties 1, tumor-derived EBI3 promotes immunosuppression by inducing CD8+ T cell exhaustion via the STAT4-IL10/CCL5 axis 4. In the tumor microenvironment, EBI3 from dendritic cells and regulatory T cells cooperatively enhances anti-tumor T cell exhaustion 56, though neoadjuvant chemotherapy can enhance anti-tumor responses partly through EBI3-expressing dendritic cells 6. These findings position EBI3 as a complex immunoregulator with potential therapeutic targeting in cancer immunotherapy 4.