SUSD2 (sushi domain containing 2) is a transmembrane protein with sushi domains that functions as a cytokine receptor with context-dependent roles in human disease. In inflammatory conditions, SUSD2 serves as a receptor for the cytokine CSBF, mediating anti-inflammatory signaling in keratinocytes by competing with TRAF6 and TNFR1 for ACT1 interaction, thereby inhibiting IL-17A/TNF-α pathways and alleviating psoriatic inflammation 1. SUSD2 exhibits cancer type-specific functions: it acts as an oncogene in breast cancer, gastric cancer, and ovarian cancer, where its expression is upregulated and correlates with poor prognosis, metastasis, and chemoresistance through mechanisms including EMT promotion and autophagy enhancement 234. Conversely, SUSD2 functions as a tumor suppressor in lung cancer and renal cell carcinoma, where it is frequently downregulated and restoration inhibits cell proliferation 5. In gastric cancer, SUSD2+ cancer-associated fibroblasts promote immunosuppression and predict poor immunotherapy response 6. Additionally, SUSD2 marks endometrial mesenchymal stem cells involved in decidualization during pregnancy 7. These findings establish SUSD2 as a multifunctional protein with potential diagnostic and therapeutic applications across multiple malignancies and inflammatory diseases.