{
  "abstract": "Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have transformed the treatment of Non-Small Cell Lung Cancer (NSCLC), yet durable responses remain limited to a minority of patients. Tumor plasticity is increasingly recognized as a determinant of immunotherapy resistance, although the tumor-intrinsic contribution of immunomodulatory mediators such as IFN-γ and PD-L1 remains poorly understood. In this review, we examine emerging evidence that IFN-γ and PD-L1, beyond their established roles in tumor-immune interactions, may contribute to the regulation of NSCLC plasticity. IFN-γ can activate non-canonical programs involving dose-dependent ICAM1/PI3K/AKT/Notch1 signaling, BCAT1- and FGF2/β-catenin-mediated metabolic reprogramming, and a putative autocrine TBX21/IL-4 signaling circuit that may sustain stem-like properties. PD-L1, in turn, is functionally integrated into plasticity-associated pathways involving the TGF-β signaling axis, β-catenin stabilization, epithelial-to-mesenchymal transition-associated microRNA networks, YAP/TAZ, CD44 and ATM signaling, as well as TRAF6/BECN1/NF-κB-dependent regulation of autophagy. Collectively, these findings support a role for IFN-γ and PD-L1 as context-dependent modulators of NSCLC plasticity, with potential implications for immunotherapy resistance, and provide a rationale for further exploring combinatorial treatment strategies and patient stratification approaches.",
  "abstract_shown": true,
  "affiliations": [
    "IRCCS Azienda Ospedaliero-Universitaria di Bologna",
    "Department of Molecular Medicine, University of Pavia",
    "Unit of Radiology, Fondazione IRCCS Policlinico San Matteo",
    "Department of Medical and Surgical Sciences (DIMEC), University of Bologna",
    "Dipartimento Oncologia − Comprehensive Cancer Center, Fondazione IRCCS Policlinico San Matteo",
    "Department of Internal Medicine and Medical Therapy, University of Pavia"
  ],
  "article_type": "review article",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Stefania Angelicola"
    },
    {
      "affs": [
        1
      ],
      "name": "Mariateresa Frascino"
    },
    {
      "affs": [
        1
      ],
      "name": "Ilaria C. Chillico"
    },
    {
      "affs": [
        1
      ],
      "name": "Patrick L. S. Michel"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Damiano Pistone"
    },
    {
      "affs": [
        3
      ],
      "name": "Maria Sofia Semprini"
    },
    {
      "affs": [
        3
      ],
      "name": "Olga Maria Pittino"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Andrea Ardizzoni"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Niccolò Leandro Alessio"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Francesco Agustoni"
    },
    {
      "affs": [
        0
      ],
      "name": "Francesco Gelsomino"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Pier-Luigi Lollini"
    },
    {
      "affs": [
        1,
        4
      ],
      "name": "Arianna Palladini"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fnea030x7r6ke.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1945729",
  "fulltext_url": "https://europepmc.org/articles/PMC13684816",
  "id": "fnea030x7r6ke",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1945729/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": "W7220847862",
  "pdf_url": "https://europepmc.org/articles/PMC13684816?pdf=render",
  "pmcid": "PMC13684816",
  "pmid": "42909957",
  "published": "2026-10-07",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/fnea030x7r6ke.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:15Z",
      "native_id": "10.3389/fimmu.2026.1945729",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1945729/full"
    },
    {
      "first_seen": "2026-10-30T12:20:14Z",
      "native_id": "MED:42909957",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42909957"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Cancer Immunotherapy and Biomarkers",
      "subfield": "oncology"
    }
  ],
  "title": "Beyond immune surveillance: IFN-γ and PD-L1 as shapers of tumor plasticity in Non-Small Cell Lung Cancer (NSCLC)",
  "title_text": "Beyond immune surveillance: IFN-γ and PD-L1 as shapers of tumor plasticity in Non-Small Cell Lung Cancer (NSCLC)",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:14Z",
  "url": "https://research.draconitic.com/paper/fnea030x7r6ke",
  "venue": "Frontiers in Immunology",
  "versions": []
}