{
  "abstract": "Background: The treatment of melanoma has been significantly improved by immune checkpoint blockade (ICB); however, primary immune resistance, particularly in PD-L1-negative tumors and in selected treatment contexts, remains a critical efficacy bottleneck. Traditional biomarkers show clear limitations in explaining resistance mechanisms and guiding clinical stratification.\n\nObjective: This review systematically proposes and elucidates the dual-ligand resistance model, comprehensively examines the molecular structure of programmed death-ligand 2 (PD-L2), its distinct dual-receptor interaction pattern with programmed death-1 (PD-1) and repulsive guidance molecule b (RGMb), and its multi-layered regulatory network, and explores the potential clinical value of PD-L2 as a context-dependent biomarker for primary immune resistance in melanoma and a potential therapeutic target.\n\nResults: Within this framework, PD-L2 may contribute to immune escape in selected contexts, particularly in PD-L1-negative tumors or after PD-L1-targeted therapy. The expression of PD-L2 is regulated by genomic, epigenetic, microenvironmental, and host factors, with evidence of subtype-specific patterns. Available data suggest that PD-L2 may provide complementary biomarker value, although supporting evidence remains heterogeneous and prospective validation is limited. Targeting the PD-L2/RGMb axis has shown potential to reverse primary resistance in preclinical models, supporting further investigation.\n\nConclusion: This synthesis positions PD-L2 as a candidate compensatory checkpoint in primary immune resistance in melanoma within a proposed dual-ligand resistance framework. However, its role should be interpreted as context dependent rather than universal. Further melanoma-specific and clinically validated studies are needed to define its biomarker and therapeutic value.",
  "abstract_shown": true,
  "affiliations": [
    "Dalian Medical University, The First Affiliated Hospital, Department of Oncology"
  ],
  "article_type": "review article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Wenjing Song"
    },
    {
      "affs": [
        0
      ],
      "name": "Yangyang Tao"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiang Ji"
    },
    {
      "affs": [
        0
      ],
      "name": "Wanting Fu"
    },
    {
      "affs": [
        0
      ],
      "name": "Xin Cai"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiu Shan"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/25qyg1a7q8p6a.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1942224",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13725200/?tool=EBI",
  "id": "25qyg1a7q8p6a",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1942224/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": [
    [
      "heading",
      "Review"
    ],
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7222941106",
  "pdf_url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1942224/pdf",
  "pmcid": "PMC13725200",
  "pmid": "42974102",
  "published": "2026-10-19",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/25qyg1a7q8p6a.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:17Z",
      "native_id": "10.3389/fimmu.2026.1942224",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1942224/full"
    },
    {
      "first_seen": "2026-11-03T15:20:50Z",
      "native_id": "PMC:PMC13725200",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13725200"
    },
    {
      "first_seen": "2026-11-04T12:23:38Z",
      "native_id": "PMC13725200",
      "source": "pmc",
      "url": "https://doi.org/10.3389/fimmu.2026.1942224"
    },
    {
      "first_seen": "2026-11-04T15:20:48Z",
      "native_id": "MED:42974102",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42974102"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Cancer Immunotherapy and Biomarkers",
      "subfield": "oncology"
    }
  ],
  "title": "Exploring the potential role of PD-L2 in primary melanoma immunotherapy resistance: a hypothesis-driven dual-ligand framework",
  "title_text": "Exploring the potential role of PD-L2 in primary melanoma immunotherapy resistance: a hypothesis-driven dual-ligand framework",
  "type": "peer-reviewed",
  "updated_at": "2026-11-05T12:21:50Z",
  "url": "https://research.draconitic.com/paper/25qyg1a7q8p6a",
  "venue": "Frontiers in Immunology",
  "versions": []
}