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Predominant mutated non-canonical tumor-specific antigens identified by proteogenomics demonstrate immunogenicity and

Haitao Xiang1, Xiangyu Guan2, Yaohua Wei3

  • 1HIM-BGI Omics Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (CAS), Hangzhou 310000, China; BGI Research, Hangzhou 310030, China; BGI Research, Shenzhen 518083, China.

Cell Genomics
|November 14, 2025
PubMed

Insights

Researchers discovered that most tumor-specific antigens (TSAs) in colorectal cancer originate from non-coding DNA. These novel TSAs effectively activate immune responses and inhibit tumor growth, paving the way for new cancer immunotherapies.

Area of Science:

  • Oncology
  • Immunology
  • Genomics

Background:

  • Tumor-specific antigens (TSAs) are key targets for T cell-mediated anti-cancer immunity.
  • Conventional TSA discovery methods, focusing on coding regions, miss potential targets in non-coding DNA.

Purpose of the Study:

  • To comprehensively identify tumor-specific antigens (TSAs) in colorectal cancer using an integrative proteogenomic approach.
  • To explore the origin and functional significance of neo-epitopes derived from both coding and non-coding genomic regions.

Main Methods:

  • Integrative proteogenomic analysis combining whole-genome sequencing, RNA sequencing, and immunoprecipitation mass spectrometry.
  • Analysis of 10 paired colorectal cancer patient samples.
  • Functional validation of identified neo-epitopes in mouse models.

Main Results:

  • Identified 96 mutated MHC class I-presented neo-epitopes, with over 80% originating from non-coding regions (intronic and intergenic).
  • Neo-epitope origins varied based on tumor mutational burden: non-coding regions in hypermutated tumors, coding variations/splicing in non-hypermutated tumors.
  • Mutated non-canonical neo-epitopes demonstrated potent CD8+ T cell activation and significant tumor growth suppression in vivo.

Conclusions:

  • Non-coding regions are a rich source of tumor-specific antigens (TSAs) in colorectal cancer.
  • The study highlights the potential of non-canonical neo-epitopes for developing novel cancer immunotherapies.
  • An integrative genomic approach is crucial for comprehensive TSA discovery and personalized treatment strategies.
Keywords:
colorectal cancerimmunopeptidomeimmunotherapyneo-epitopeproteogenomicstumor-specific antigens

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