2026 Volume 34 Issue 2 Pages 65-73
Background: Human endogenous retroviruses (HERVs) constitute approximately eight per cent of the human genome and are transcriptionally silenced in most healthy somatic tissues. Their reactivation in malignancy generates a distinctive class of tumour-associated peptides capable of engaging CD8+ T-cell immunity through HLA class I presentation. Tumour mutational burden, mismatch repair deficiency, and PD-L1 expression have dominated immune checkpoint inhibitor (ICI) biomarker frameworks, yet the host HLA class I genotype is increasingly recognised as a structural determinant of immune visibility whose role in shaping the HERV-derived immunopeptidome remains under-investigated.
Scope: This review synthesises the molecular basis of HLA class I-restricted HERV peptide presentation, examines convergent evidence from immunopeptidomic, computational, and clinical ICI cohort studies, and proposes an integrated framework in which HLA genotype gates HERV-mediated antitumour immunity. Because HERV expression and HLA presentation capacity are also modulated by radiotherapy, cytotoxic chemotherapy, and targeted agents, their relevance is considered across the broader anticancer treatment landscape rather than ICI alone.
Key insights: (i) Cancer-restricted HERV transcripts give rise to a partially shared, partially private peptide repertoire, much of it predicted to bind common HLA-A and HLA-B alleles with high affinity. (ii) HLA class I heterozygosity, evolutionary divergence (HED), and the absence of HLA loss of heterozygosity each modulate the breadth of presentable HERV peptides, paralleling their established influence on neoantigen-driven immunity. (iii) HERV expression independently predicts ICI response in clear cell renal cell carcinoma and across pan-cancer immune-active phenotypes, with emerging data suggesting this effect is conditioned by HLA genotype. (iv) Radiotherapy and DNA-damaging chemotherapy induce HERV transcription and HLA class I upregulation through overlapping viral-mimicry and immunogenic cell death pathways, extending the HLA–HERV axis beyond ICI to combination strategies with surgery, radiotherapy, and targeted therapy.
Conclusion: Integrating HLA class I genotype into HERV-based biomarker strategies is a tractable refinement of patient selection across immunotherapy, radiotherapy, and systemic treatment, and a rational design principle for HERV-targeted vaccines and TCR-engineered T-cell therapies. Specific research priorities are proposed, including HLA-stratified immunopeptidomic atlases of HERV peptides, HLA-aware HERV scoring pipelines, and prospective validation across treatment modalities.
