Systems serology identifies differential pan-viral seroreactivity profiles associated with healthy aging and cancer

Abstract A viral exposure signature (VES) has previously been shown to predict the development of hepatocellular carcinoma (HCC) in at-risk individuals through comprehensive serological profiling using the VirScan platform. Whether cumulative antimicrobial immune histories are associated with cancer status across multiple malignancies remains unknown. We applied high-throughput VirScan systems serology to characterize antibody reactivities against a comprehensive microbial peptide library in 359 participants, including 172 patients with cancer and 187 healthy individuals. To account for age-related immune remodeling, healthy participants were stratified into adults ( < 70 years) and exceptionally healthy elderly individuals ( > 80 years, including nonagenarians and centenarians). Differential Pan-viral Seroreactivity Profiles (DPSPs) were identified through an unbiased statistical workflow combining differential class comparison, feature selection, predictive modeling, cross-validation, and receiver operating characteristic (ROC) curve analysis. Distinct DPSPs discriminated healthy individuals from patients with cancer. The identified signatures comprised antibody reactivities against peptides derived predominantly from persistent herpesviruses, acute respiratory viruses and, consistently across multiple comparisons, human respiratory syncytial virus (HRSV). Remarkably, healthy elderly individuals generally exhibited higher antibody titers than patients with cancer, whereas healthy adults showed the opposite pattern. These differential serological signatures supported accurate class prediction in several comparisons, indicating that cumulative antimicrobial immune histories differ according to health status after accounting for physiological immune aging. Our findings demonstrate that lifelong cumulative antimicrobial immune history generates reproducible serological signatures associated with healthy aging and cancer status. Although the present cross-sectional study does not establish causal biological protection, it identifies hypothesis-generating biomarkers that warrant validation in independent prospective cohorts and supports the potential value of comprehensive serological profiling for future cancer risk stratification.