{
  "abstract": "T cell activation relies on the coordinated integration of T cell receptor (TCR) and cosignaling pathways, yet how these signals are physically organized remains unclear. Here, we demonstrate that CD28 co-stimulation is driven by a condensation mechanism in which the CD28 intracellular domain (ICD) forms signaling condensates with the Src-family kinase Lck. Ligand engagement promotes CD28 ICD accessibility and triggers rapid CD28/Lck condensation, enhancing CD28 phosphorylation, cytoskeletal polarization, and cytokine production. The downstream effectors of CD28, including PI3K and GRB2, can also be recruited into the CD28-Lck condensates in our reconstituted system. We further identify PD-1 as a graded regulator of this process: Monophosphorylated PD-1 is recruited into CD28/Lck condensates, whereas diphosphorylated PD-1 competitively binds the CD28 ICD and dissolves these assemblies. CD28 and PD-1 ICDs also undergo condensation directly, revealing a dynamic and compositionally heterogeneous signaling system. Guided by this competitive condensation mechanism, we engineer CD28 ICD mutants that preserve Lck condensation while resisting PD-1-mediated disruption. Incorporation of these condensation-selective mutants into Chimeric antigen receptor (CAR) constructs confers resistance to inhibitory signaling and enhances antitumor efficacy in vivo. These findings establish condensation as a central organizing principle of CD28 costimulation and provide a biophysical framework for engineering more resilient therapeutic T cells.",
  "abstract_shown": true,
  "affiliations": [
    "State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China",
    "College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China",
    "Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China",
    "Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150001, Heilongjiang, China",
    "Department of Cardiology of the Second Affiliated Hospital and Department of Cell Biology, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, Zhejiang, China",
    "Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, Zhejiang, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Hui Chen",
      "orcid": "0000-0003-1642-621X"
    },
    {
      "affs": [
        0
      ],
      "name": "Songfang Wu",
      "orcid": "0000-0003-0553-3415"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yong Zhang"
    },
    {
      "affs": [
        2
      ],
      "name": "Wei Hu"
    },
    {
      "affs": [
        3
      ],
      "name": "Changjie Lou"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Wei Chen",
      "orcid": "0000-0001-5366-7253"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Jizhong Lou",
      "orcid": "0000-0003-4031-6125"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ajdatbt68jwsx.bib",
  "cited_by": 0,
  "doi": "10.1073/pnas.2612742123",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13715824/",
  "id": "ajdatbt68jwsx",
  "issns": [
    "0027-8424",
    "1091-6490"
  ],
  "landing_url": "https://doi.org/10.1073/pnas.2612742123",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "420"
    ],
    [
      "heading",
      "Biological Sciences"
    ],
    [
      "heading",
      "Immunology and Inflammation"
    ],
    [
      "heading",
      "Sdg-3-Good-Health-and-Well-Being"
    ],
    [
      "openalex",
      "2403|T-cell and B-cell Immunology"
    ]
  ],
  "openalex": "W7223127088",
  "pdf_url": null,
  "pmcid": "PMC13715824",
  "pmid": "42905561",
  "published": "2026-10-21",
  "publisher": "National Academy of Sciences",
  "ris": "https://research.draconitic.com/paper/ajdatbt68jwsx.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T12:23:01Z",
      "native_id": "PMC13715824",
      "source": "pmc",
      "url": "https://doi.org/10.1073/pnas.2612742123"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|T-cell and B-cell Immunology",
      "subfield": "immunology"
    }
  ],
  "title": "CD28 costimulation is organized by signaling condensates and counteracted by PD-1",
  "title_text": "CD28 costimulation is organized by signaling condensates and counteracted by PD-1",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:23:01Z",
  "url": "https://research.draconitic.com/paper/ajdatbt68jwsx",
  "venue": "Proceedings of the National Academy of Sciences of the United States of America",
  "versions": []
}