From:  Next-generation cancer vaccines: targeting cryptic and non-canonical antigens for precision immunotherapy

 MHC presentation of cryptic (non-canonical) and canonical antigens.

MHC presentation aspectCanonical antigensCryptic (non-canonical) antigens
Source of antigenDerived from well-annotated coding regions (exons), stable, long-lived proteins.Derived from non-coding regions, frameshifts, introns, UTRs, or aberrant translation, typically short-lived proteins.
Processing pathway (MHC-I)Proteasomal degradation followed by TAP-mediated peptide transport to the ER generates typical 8–10 aa peptides.May bypass classical proteasomal cleavage; often only require N-terminal methionine removal; favor 8-mers over 10-mers.
Binding to MHC moleculesGenerally strong and predictable based on established binding motifs and allele preferences.Cryptic antigens often bind uniquely, showing stable binding, especially to HLA-B alleles, and differ in terminal aa usage.
Presentation efficiencyAbundant and well-presented due to stable protein origins and conventional processing.Enriched in MHC-I immunopeptidome despite low abundance in whole-cell proteome; efficient due to rapid degradation.
Immunological visibilityMore likely to be recognized as “self” by the immune system, limiting T cell activation due to central tolerance.Escaping central tolerance makes it more likely to be recognized as foreign, enabling strong immune responses.
Clinical relevanceCommonly targeted in traditional cancer vaccines, they have limited success due to immune tolerance and tumour escape mechanisms.Emerging targets for personalized vaccines are promising due to their tumour-specificity and high immunogenicity.
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MHC: major histocompatibility complex; TAP: transporter associated with antigen presentation; ER: endoplasmic reticulum; aa: amino acids; UTR: untranslated region; HLA: human leukocyte antigen.