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Cryptic but critical: non-canonical antigens in cancer immunotherapy

Gabriel Goncalves1, Riccardo Dolcetti2, Joshua D Ooi3

  • 1Department of Medicine, School of Clinical Science, Faculty of Medicine, Nursing & Health Science, Monash University, Clayton, VIC, Australia; Monash Proteomics & Metabolomics Platform, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia.

Trends in Immunology
|June 19, 2025
PubMed

Insights

Cancer immunotherapies face challenges as non-canonical antigens from noncoding regions are key. Emerging strategies like cryptic antigen and T-cell receptor (TCR)-targeted vaccines offer new personalized and off-the-shelf cancer treatment options.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Research

Background:

  • Recent studies reveal non-canonical antigens from unmutated, noncoding regions are prevalent in cancer immunopeptidomes.
  • This finding challenges the traditional focus on mutation-driven cancer neoantigens.

Purpose of the Study:

  • To discuss the implications of non-canonical antigens in cancer immunology.
  • To highlight novel therapeutic strategies beyond mutation-centric approaches.

Main Methods:

  • Review and discussion of recent findings on cancer immunopeptidomes.
  • Analysis of emerging immunotherapy strategies targeting non-canonical antigens.

Main Results:

  • Non-canonical antigens, not derived from mutations, are dominant in many cancer immunopeptidomes.
  • Conventional mutation-centric immunotherapies may not fully address the tumor immune response.

Conclusions:

  • Emerging strategies like cryptic antigen vaccines and TCR-targeted vaccines show promise.
  • These novel approaches offer new avenues for personalized and off-the-shelf cancer immunotherapy.

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