{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:00:56Z","timestamp":1791302456474,"version":"4.1.0"},"reference-count":93,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173385"],"award-info":[{"award-number":["82173385"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The clinical success of immune checkpoint blockade (ICB) in oncology has validated the existence of molecular brakes that restrain T-cell immunity. While releasing these brakes unleashes antitumour responses, their physiological role is to maintain self-tolerance. This review explores the reciprocal paradigm of the CD160\u2013HVEM axis across three disease settings: immuno-oncology, autoimmunity and transplantation. CD160\u2013HVEM signalling can enforce pathological T-cell exhaustion in cancer, yet its failure or costimulatory co-option can precipitate autoimmunity or accelerate allograft rejection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Mechanisms<\/jats:title>\n                    <jats:p>Unlike programmed cell death protein 1 (PD-1), CD160 operates within a bidirectional network involving herpesvirus entry mediator (HVEM; TNFRSF14), B- and T-lymphocyte attenuator (BTLA) and LIGHT (TNFSF14). The axis is expressed across lymphocytes, myeloid cells, epithelium, endothelium and malignant B cells. Mouse and human biology of the axis are not interchangeable: murine CD160 is a broad major histocompatibility complex (MHC) class I and CD1d receptor, whereas human natural killer (NK) triggering is dominated by HLA-C, and the transmembrane isoform CD160-TM is human-characterised. Structural diversity, from an inhibitory glycosylphosphatidylinositol (GPI)-anchored form to activating CD160-TM on NK cells, positions CD160 as a tunable rheostat rather than a linear checkpoint.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Therapeutic implications<\/jats:title>\n                    <jats:p>While direct anti-CD160 candidates remain in advanced preclinical development, other components of the HVEM network are undergoing human clinical testing. The most mature clinical programme is tifcemalimab, an anti-BTLA monoclonal antibody, not an anti-CD160 agent. Antagonistic anti-HVEM antibodies (Demerl\u00e9 anti-HVEM18\u201310 in humanised mice; preclinical fully human 4CB1, mechanistically related but distinct) block HVEM engagement by both BTLA and CD160. Because CD160 is inhibitory on T cells but activating on NK cells via CD160-TM, a systemic antibody to the shared ectodomain is a dual-function drug-design constraint, not a simple checkpoint blockade.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Precision use of this axis requires isoform, cell type, interaction geometry and disease context to be specified before a direction of intervention is chosen. Next steps are biomarker-qualified enrichment, isoform-discriminating reagents, and correlative CD160 profiling inside ongoing BTLA\u2013HVEM studies. Pathological exhaustion that shields tumours remains a map for restoring tolerance in autoimmunity and for blocking CD28-independent rejection in transplantation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1782124","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:48:30Z","timestamp":1791301710000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The CD160\u2013HVEM axis at the crossroads of tolerance and immunity: lessons from cancer for autoimmunity and transplantation"],"prefix":"10.3389","volume":"17","author":[{"given":"Shulin","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Urology, Peking University Third Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulin","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Urology, Peking University Third Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/B978-0-323-54948-6.00001-9","article-title":"Immune checkpoint inhibitors","volume-title":"Immune Checkpoint Inhibitors in Cancer","author":"Kalinski","year":"2019"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00418","article-title":"Beyond CTLA-4 and PD-1, the Generation Z of negative checkpoint regulators","volume":"6","author":"Le Mercier","year":"2015","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2018.01.010","article-title":"Autoimmune phenomena and disease in cancer patients treated with immune checkpoint inhibitors","volume":"17","author":"Tocut","year":"2018","journal-title":"Autoimmun Rev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.01.017","article-title":"Primary, adaptive, and acquired resistance to cancer immunotherapy","volume":"168","author":"Sharma","year":"2017","journal-title":"Cell"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2201445","article-title":"PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer","volume":"386","author":"Cercek","year":"2022","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0312-6","article-title":"Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade","volume":"20","author":"Miller","year":"2019","journal-title":"Nat Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0910528","article-title":"Regulation of inflammation, autoimmunity, and infection immunity by HVEM-BTLA signaling","volume":"89","author":"Shui","year":"2011","journal-title":"J Leukoc Biol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2009.00783.x","article-title":"The CD160, BTLA, LIGHT\/HVEM pathway: a bidirectional switch regulating T-cell activation","volume":"229","author":"Cai","year":"2009","journal-title":"Immunol Rev"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2011.01064.x","article-title":"The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation","volume":"244","author":"Steinberg","year":"2011","journal-title":"Immunol Rev"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-019-0241-1","article-title":"HVEM, a cosignaling molecular switch, and its interactions with BTLA, CD160 and LIGHT","volume":"16","author":"Rodriguez-Barbosa","year":"2019","journal-title":"Cell Mol Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"63","DOI":"10.4049\/jimmunol.182.1.63","article-title":"Identification and characterization of a transmembrane isoform of CD160 (CD160-TM), a unique activating receptor selectively expressed upon human NK cell activation","volume":"182","author":"Giustiniani","year":"2009","journal-title":"J Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.113694","article-title":"CD160 protein as a new therapeutic target in a battle against autoimmune, infectious and lifestyle diseases. 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