Predicting immunotherapy benefit in leiomyosarcoma through active chromatin cfDNA profiling

Leiomyosarcoma (LMS) is an aggressive soft-tissue sarcoma characterized by epigenomic dysregulation and variable responsiveness to checkpoint inhibitors (CPIs). In this study, we evaluated a novel liquid biopsy platform based on circulating cell-free DNA active chromatin (cfDNA_ac) profiling to identify baseline biomarkers associated with clinical benefit rate (CBR) in 30 LMS patients treated with durvalumab plus olaparib or cediranib. A total of 1,570 molecular features across genomic regions were identified, and recursive feature elimination was applied to select discriminative cfDNA_ac signatures. Patients achieving CBR demonstrated enrichment of pathways related to cell death, interferon-γ signaling, and immune activation. Signatures reflecting B-cell activation, T-cell activation, and extracellular matrix organization were significantly associated with improved progression-free survival (PFS; p < 0.05). In contrast, a baseline tumor fraction >5% was negatively associated with CBR (p = 0.041) and correlated with inferior PFS (p = 0.008). Distinct copy number variation profiles further characterized patients with CBR and were significantly associated with PFS. In this analysis, cfDNA_ac profiling represents a promising non-invasive strategy to predict clinical benefit from CPI-based therapy in LMS. Prospective validation in independent cohorts is warranted to clarify its clinical utility.