Multimodal AI for Single cfDNA Profiling and Cancer Screening

Cell-free DNA (cfDNA) serves as a non-invasive biomarker for cancer detection, but conventional methods face challenges due to the ultra-low abundance of tumor-derived cfDNA (ctDNA) among normal cfDNA. Though nucleosome-bound cfDNA harbors rich epigenomic features that could enable ctDNA identification by single-molecule multi-omics cross-validation, this remains unexplored due to methodological limits. Here, we developed a cfDNA sequencing approach integrating methylation, fragmentomics, and histone modifications at the single-molecule level; together with gene semantics and epigenomic annotations, these modalities were vectorized and fused to represent each cfDNA molecule. We trained a Transformer-based model (cfAI) to profile and evaluate ctDNA likelihood at molecule, gene, and sample levels. cfAI achieved ∼10-fold enrichment of cancer-derived signals over noise and reached 72.6% sensitivity at 93.1% specificity for multi-cancer detection. Our study establishes an innovative framework that overcomes the inherent signal-to-noise limitations of conventional assays and reveals biological features at molecular resolution for cancer detection.