{
  "abstract": "Background: 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–HVEM axis across three disease settings: immuno-oncology, autoimmunity and transplantation. CD160–HVEM signalling can enforce pathological T-cell exhaustion in cancer, yet its failure or costimulatory co-option can precipitate autoimmunity or accelerate allograft rejection.\n\nMechanisms: 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.\n\nTherapeutic implications: 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 (Demerlé anti-HVEM18–10 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.\n\nConclusion: 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–HVEM studies. Pathological exhaustion that shields tumours remains a map for restoring tolerance in autoimmunity and for blocking CD28-independent rejection in transplantation.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Urology, Peking University Third Hospital"
  ],
  "article_type": "research support, non u.s. gov't",
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Shulin Sun"
    },
    {
      "affs": [
        0
      ],
      "name": "Lulin Ma"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ejey7czh38012.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1782124",
  "fulltext_url": "https://europepmc.org/articles/PMC13682303",
  "id": "ejey7czh38012",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1782124/full",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7220728709",
  "pdf_url": "https://europepmc.org/articles/PMC13682303?pdf=render",
  "pmcid": "PMC13682303",
  "pmid": "42903704",
  "published": "2026-10-06",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/ejey7czh38012.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:15Z",
      "native_id": "10.3389/fimmu.2026.1782124",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1782124/full"
    },
    {
      "first_seen": "2026-10-30T12:19:57Z",
      "native_id": "MED:42903704",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42903704"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Cancer Immunotherapy and Biomarkers",
      "subfield": "oncology"
    }
  ],
  "title": "The CD160–HVEM axis at the crossroads of tolerance and immunity: lessons from cancer for autoimmunity and transplantation",
  "title_text": "The CD160–HVEM axis at the crossroads of tolerance and immunity: lessons from cancer for autoimmunity and transplantation",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:57Z",
  "url": "https://research.draconitic.com/paper/ejey7czh38012",
  "venue": "Frontiers in Immunology",
  "versions": []
}