ZNF683 (zinc finger protein 683) is a transcriptional repressor that functions as a master regulator of tissue-resident lymphocyte identity and anti-tumor immunity. It binds DNA within promoter regions to regulate gene expression programs in CD8+ T cells and natural killer (NK) cells 1. ZNF683 marks a distinct population of intermediate exhausted CD8+ effector/memory T cells that retain cytotoxic potential and express key genes including TCF7, LMO2, and CD69 2. In tissue-resident settings, ZNF683 is required for NK cell tissue imprinting and ILC1 development independent of the NK-specifying factor EOMES 3. Clinically, ZNF683+ CD8+ T cells associate strongly with immunotherapy response across multiple cancer types. Patients with Richter syndrome and head and neck cancer experiencing response to anti-PD-1 therapy show enriched preexisting ZNF683+CTX+ tumor-infiltrating lymphocytes 21. Similarly, ZNF683+ CD8+ cells predict favorable outcomes in acute myeloid leukemia treated with donor lymphocyte infusion, where these cells coordinate antitumor immunity within bone marrow microenvironments 4. However, elevated ZNF683 expression in certain contexts (such as KRAS/STK11 co-mutant lung cancers) may indicate tumor residence phenotypes potentially detrimental to systemic anti-tumor responses 5. ZNF683 represents a biomarker for identifying T cells with therapeutic potential and a mechanistic target for optimizing immunotherapy strategies.