Human endogenous retroviruses as immune-related prognostic biomarkers in pancreatic cancer

BACKGROUND: Human endogenous retroviruses (HERVs) may modulate antitumor immunity and prognosis in pancreatic cancer (PC), but reported findings remain heterogeneous. METHODS: A systematic review was conducted according to PRISMA guidelines. PubMed/MEDLINE and grey literature were searched for studies reporting HERV expression in PC. Extracted data included HERV family and genomic region, detection methods, biological specimens, immune correlations, clinicopathologic associations, and survival outcomes. RESULTS: Eleven studies were included, reporting 1,085 PC cases among 9,241 cancer patients. HERV-H was evaluated in 6 studies, HERV-K in 3, and 2 studies did not specify family. Elements included env sequences (3 studies), envelope proteins (2), LTR sequences (6), and LTR-derived proteins (HHLA2 (5). Detection methods comprised RNA-seq (n = 7 studies), PCR/qPCR (n = 7), immunohistochemistry (n = 6), western blot (n = 4), and ELISA (n = 4). HERV detection ranged from 16.7% to ~ 80%, varying with the sequence and laboratory method. Immune correlations were described in 7 studies, including associations with CD8⁺ T-cell infiltration, cytokines (IL-2, TNF-α, IFN-γ), PD-1/PD-L1, and anti-HERV antibodies. Overall survival was reported in 6 studies, with both adverse (HR 1.26-2.24) and favourable (HR 0.47-0.66) associations reported, particularly for HERV-H derived LTR products (HHLA2). CONCLUSIONS: HERVs exhibit frequent, target-dependent expression patterns that trigger proinflammatory activation. Within these families, HERV-H derived LTR elements, specifically HHLA2, demonstrate the most consistent correlation with increased T-cell infiltration and favorable survival, supporting their potential as prognostic biomarkers.