{
  "abstract": "Background Renal cell carcinoma (RCC) frequently exhibits favorable responses to immunotherapy, despite a low tumor mutational burden, suggesting a critical role for non-mutational antigens presented by human leukocyte antigen class I in activating CD8 + T cells.Methods To systematically identify non-canonical tumor-specific antigens, we developed an integrated proteogenomic approach to RCC samples by combining immunopeptidomics with exome and transcriptome sequencing. We subsequently primed and expanded antigen-reactive T cells in vitro, isolated a panel of antigen-specific T-cell receptors, and characterized their functionality. Finally, we investigated the tumor-killing and regression of non-canonical antigen-reactive T cells using patient-derived tumor-like cell clusters and mouse models.Results We discovered a diverse repertoire of non-canonical tumor-specific antigens derived from human endogenous retroviruses (hERVs) and long non-coding RNAs (lncRNAs), many of which were shared across patients. Single-cell RNA sequencing further revealed that T cells reactive to these antigens were enriched within exhausted subsets in the tumor microenvironment, indicative of persistent antigen-specific stimulation. Functionally, T cells engineered to recognize these non-canonical antigens mediated potent tumor cell killing both in vitro and in vivo. Our findings establish hERV-derived and lncRNA-derived antigens as key drivers of RCC immunogenicity and highlight their strong potential as targets for T-cell-based immunotherapy.Conclusions Our work is the first to demonstrate that non-canonical antigens drive immunogenicity in low-mutation RCC, thereby resolving a key question in cancer immunology—how tumors with low mutational burden can provoke robust T-cell responses.",
  "authors": [
    {
      "affiliations": [
        "State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China"
      ],
      "name": "Jiahao Wang"
    },
    {
      "affiliations": [
        "Department of Urology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Yihao Zhu"
    },
    {
      "affiliations": [
        "State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China"
      ],
      "name": "Xinyu He"
    },
    {
      "affiliations": [
        "State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China"
      ],
      "name": "Shenyi Yin"
    },
    {
      "affiliations": [
        "State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China"
      ],
      "name": "Yang He"
    },
    {
      "affiliations": [
        "Innovative Vaccine and Immunotherapy Research Center, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Pengju Yao"
    },
    {
      "affiliations": [
        "State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China"
      ],
      "name": "Juan Li"
    },
    {
      "affiliations": [
        "Department of Urology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Xuwen Li"
    },
    {
      "affiliations": [
        "State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China"
      ],
      "name": "Peiting Shi"
    },
    {
      "affiliations": [
        "State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China"
      ],
      "name": "Renzhi Qian"
    },
    {
      "affiliations": [
        "State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China"
      ],
      "name": "Zhiqing Xiao"
    },
    {
      "affiliations": [
        "Department of Urology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Xiongjun Ye"
    },
    {
      "affiliations": [
        "State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China"
      ],
      "name": "Jianzhong Jeff Xi"
    },
    {
      "affiliations": [
        "State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Organoid and Digital Tumor Twin, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China"
      ],
      "name": "Buqing Ye"
    }
  ],
  "title": "Targeting non-canonical antigens unlocks functional T-cell responses in renal cell carcinoma",
  "uid": "b1bd4e38-7fc1-58e3-8264-a7661ef68821"
}