SUSD6 (sushi domain containing 6) is a membrane-associated negative regulator of MHC-I antigen presentation with critical roles in cancer immune evasion and cellular senescence. Mechanistically, SUSD6 forms a trimolecular complex with transmembrane protein TMEM127 and MHC-I, recruiting the E3 ubiquitin ligase WWP2 to promote MHC-I ubiquitination and lysosomal degradation 1. SUSD6 functions as a co-disinhibitory adaptor that activates WWP2 through its PY motif, working together with TMEM127 to relieve WWP2 autoinhibition 2. In cancer biology, SUSD6 is abundantly expressed in acute myeloid leukemia and solid tumors, where its ablation enhances MHC-I presentation and reduces tumor growth in a CD8+ T cell-dependent manner 1. The SUSD6/TMEM127/WWP2 gene signature negatively correlates with cancer survival, establishing this axis as a potential immunotherapy target 1. In cellular senescence, SUSD6 expression is downregulated during inflammageing-induced cell cycle arrest in human gingival fibroblasts exposed to pro-inflammatory stimuli 3. Clinically, SUSD6 represents a promising therapeutic target for overcoming immune checkpoint blockade resistance in both hematologic and solid malignancies through restoration of anti-tumor T cell immunity.