WDFY4 is a BEACH domain-containing protein essential for cross-presentation of viral and tumor antigens to CD8+ T cells by classical dendritic cells (cDC1s) 1. The protein acts near the plasma membrane to promote endosomal-to-cytosol antigen trafficking, enabling presentation of cell-associated antigens 1. Recent evidence demonstrates WDFY4 also regulates cross-presentation of immune complexes by both cDC1 and cDC2 subsets through a shared WDFY4-dependent pathway 2. Beyond antigen presentation, WDFY4 plays roles in B-cell survival and differentiation, particularly during later B-cell maturation phases in lung adenocarcinoma 3. In disease contexts, WDFY4 variants associate with systemic lupus erythematosus (SLE), rheumatoid arthritis, and primary biliary cholangitis across diverse populations 4. Notably, dysregulated truncated WDFY4 isoforms enhance MDA5-mediated signaling in clinically amyopathic dermatomyositis 5. Additionally, WDFY4 regulates ferroptosis through the LAPTM5/CDC42/mTOR/4EBP1/SLC7A11 pathway, with elevated expression promoting atherosclerosis progression 6. In lupus nephritis, elevated serum WDFY4 serves as a specific biomarker 7, while downregulated WDFY4 in lung adenocarcinoma correlates with poor prognosis 3.