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A mounting body of evidence indicates that CD8 T cell differentiation into functionally different subsets, such as effector, memory, tissue-resident memory, and exhausted T cells, is controlled by a group of nuclear receptors (NRs). NRs sense signals from various physiological and environmental cues, such as nutritional, endocrine, stress\/circadian, and metabolic signals, and translate them into gene-regulatory decisions. NRs act through direct and indirect DNA binding, corepressor\u2013coactivator exchange, and transrepression of effector-associated transcription factors, thereby reshaping chromatin accessibility and metabolic programs during CD8 T cell differentiation. This review highlights major CD8 T cell-regulating pathways involving vitamin A\u2013sensing RAR-\u03b1, sterol-responsive LXR-\u03b2 and ROR-\u03b1, orphan NR4A proteins; vitamin D receptor (VDR), glucocorticoid receptor (GR), and androgen receptor (AR). Understanding the shared and separable functions of NRs and their ligands provides insights into therapeutic strategies, such as pharmacologic modulation, checkpoint blockade, and chimeric antigen receptor T cell therapies, to promote durable antitumor and antiviral CD8 T cell activities.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag261","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:03:21Z","timestamp":1790899401000},"source":"Crossref","is-referenced-by-count":0,"title":["Context-dependent regulation of cytotoxic T lymphocytes by nuclear receptors"],"prefix":"10.1093","volume":"215","author":[{"given":"Chang H","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Michigan School of Medicine , Ann Arbor, MI,","place":["United States"]},{"name":"Mary H. Weiser Food Allergy Center, University of Michigan School of Medicine , Ann Arbor, MI,","place":["United States"]},{"name":"Immunology Graduate Program, University of Michigan , Ann Arbor, MI,","place":["United States"]},{"name":"Rogel Cancer Center, University of Michigan School of Medicine , Ann Arbor, MI,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"2026100123361811500_vkag261-B1","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.1016\/j.immuni.2023.09.005","article-title":"CD8(+) T cells in the cancer-immunity cycle","volume":"56","author":"Giles","year":"2023","journal-title":"Immunity"},{"key":"2026100123361811500_vkag261-B2","doi-asserted-by":"publisher","first-page":"eadg3868","DOI":"10.1126\/sciimmunol.adg3868","article-title":"Cellular and molecular waypoints along the path of T cell 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