IFI35 (interferon-induced protein 35) functions as a pleiotropic immune regulator with context-dependent roles in innate immunity and cancer. Intracellularly, IFI35 associates with NMI in response to interferon-alpha to regulate immune signaling 12. The IFI35-NMI complex inhibits virus-triggered type I interferon production and negatively regulates NF-κB signaling by blocking p65/RELA nuclear translocation, thereby inhibiting endothelial cell proliferation 34. Extracellularly, IFI35 functions as a damage-associated molecular pattern (DAMP); macrophage-secreted IFI35 activates NF-κB signaling in adjacent macrophages through TLR4, promoting pro-inflammatory cytokine release 5. In lupus nephritis, IFI35 is hypomethylated and promotes mesangial cell proliferation via the IFNγ/STAT1 pathway 67. In cancer contexts, IFI35 exhibits dual roles: it promotes CD8+ T cell proliferation and cytotoxicity in colorectal cancer 8, enhances vaccine efficacy in renal carcinoma 9, and maintains glioblastoma stem cells and M1 macrophage differentiation 1011. Conversely, IFI35 suppresses antitumor immunity in triple-negative breast cancer by promoting CCL2-mediated myeloid-derived suppressor cell infiltration 12, and promotes renal cancer progression by inhibiting STAT1/STAT6-dependent autophagy 13. These findings establish IFI35 as a context-dependent immune regulator with potential therapeutic relevance across multiple diseases.