Integrating immunopeptidomics with liquid biopsy for precision oncology.

In cancer immunotherapy, peptide-major histocompatibility complexes are increasingly exploited as precise therapeutic targets. For instance, T-cell receptor (TCR)-engineered T cells, peptide vaccines, and TCR-mimic antibodies leverage the direct recognition of tumor-specific or tumor-associated antigens presented on human leukocyte antigen (HLA) molecules, offering highly specific and effective approaches to eliminate malignant cells. Classical immunopeptidomic studies rely on tumor tissue samples to identify targetable peptides; however, tissue accessibility and tumor heterogeneity remain major limitations. Liquid biopsy, including circulating tumor cells, extracellular vesicles, and cell-free nucleic acids, represents a minimally invasive alternative to capture tumor-derived material. Recent methodological adaptations allow applying immunopeptidomics to these circulating biomarkers to profile HLA-bound peptides in blood. Integrating immunopeptidomics with liquid biopsy could expand the scope of precision oncology, providing dynamic, patient-specific insights into antigen presentation for developing and monitoring personalized immunotherapies in a minimally invasive manner.