{
  "abstract": "Background Chimeric antigen receptor (CAR) T-cell therapy has achieved clinical success in hematologic malignancies, but remains limited in solid tumors due to immune checkpoint-mediated suppression and intrinsic signaling constraints. Unlike T-cell receptors (TCRs), CARs fail to efficiently recruit the linker for activation of T cells (LAT) signalosome, resulting in suboptimal signal propagation and unstable immunological synapse organization.Methods To address this limitation, we engineered a programmed cell death protein 1 (PD-1)–LAT (PLAT) chimeric switch scaffold that couples PD-1 engagement to LAT-dependent proximal signaling. We compared the signaling kinetics, synaptic architecture, and antitumor efficacy of PLAT-expressing HER2 CAR T cells against those expressing conventional PD-1-CD28 switch receptors or dominant-negative PD-1 using biochemical signaling assays, quantitative imaging analysis, chronic antigen stimulation models, and in vivo xenograft validation.Results PLAT enhanced LAT phosphorylation and nucleated LAT-associated signaling complexes on programmed death-ligand 1 engagement. This reorganized the CAR immune synapse into a concentric, TCR-like architecture, restoring proximal signaling strength. This signaling reprogramming resulted in increased calcium flux and NFAT/NF-κB activation, driving enhanced cytotoxicity, sustained proliferation, and resistance to functional exhaustion under chronic antigen exposure. In direct comparisons, PLAT outperformed conventional PD-1–CD28 switch receptors in early functional responses and demonstrated superior functional durability and antitumor activity in vivo compared with dominant-negative PD-1 strategies.Conclusions These findings establish PLAT as a scaffold-based strategy that directly addresses intrinsic CAR signaling deficiencies by converting immune checkpoint engagement into LAT-dependent proximal signaling restoration. This work provides a new framework for engineering CAR T cells with improved function and persistence in immunosuppressive tumor environments.",
  "authors": [
    {
      "affiliations": [
        "Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Daejeon, Korea (the Republic of)",
        "Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Korea (the Republic of)"
      ],
      "name": "Cho I Park"
    },
    {
      "affiliations": [
        "Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Daejeon, Korea (the Republic of)"
      ],
      "name": "Segi Kim"
    },
    {
      "affiliations": [
        "Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Daejeon, Korea (the Republic of)"
      ],
      "name": "Hwanyong Shim"
    },
    {
      "affiliations": [
        "Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Daejeon, Korea (the Republic of)"
      ],
      "name": "Minh Ha Nguyen"
    },
    {
      "affiliations": [
        "Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Daejeon, Korea (the Republic of)",
        "KAIST Stem Cell Research Center, Korea Advanced Institute of Science and Technology, Daejeon, Daejeon, Korea (the Republic of)"
      ],
      "name": "Won-ki Cho"
    },
    {
      "affiliations": [
        "Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Korea (the Republic of)",
        "School of Transdisciplinary Innovations, Seoul National University, Gwanak-gu, Seoul, Korea (the Republic of)"
      ],
      "name": "Chan Hyuk Kim"
    }
  ],
  "title": "Chimeric switch scaffold protein augments CAR synapse formation and signaling networks",
  "uid": "8f134e7f-5e2e-5b5a-8685-7a2e896b6bee"
}