BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is one of the most devastating outcomes of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This remains an area of unmet clinical need for optimal therapy for BOS patients partly due to the limited understanding of pathogenic mechanisms. METHODS: We collected blood samples from 22 patients with cGVHD and 11 patients without cGVHD following allo-HSCT. By applying a combination of mass cytometry (CyTOF), RNA-sequencing and the quantitative cytokine array, we discovered a new cellular hallmarker of patients with cGVHD-BOS. This finding was further validated in cGVHD-BOS murine models by using single-cell RNA sequencing (scRNA-seq) and paired single-cell V(D)J sequencing analyses. FINDINGS: We revealed that circulating Granzyme K (GZMK)-expressing CD8 INTERPRETATION: This study provides proof-of-principle evidence for clonal GZMK FUNDING: This work was supported by the National Natural Science Foundation of China (No. 82170141, 82100123, 81870136), and "Pioneer" and "Leading Goose" R&D Program of Zhejiang (grant No. 2022C03012).