Single-cell sequencing uncovers clonal dynamics profiles and therapeutic resistance biomarkers in relapsed and refractory peripheral T-cell lymphoma

Peripheral T-cell lymphoma (PTCL) is a heterogeneous and highly aggressive subtype of non-Hodgkin lymphoma. Approximately 30% of patients develop relapsed or refractory (R/R) PTCL due to disease recurrence or failure to achieve complete remission after first-line therapy. The molecular and cellular mechanisms underlying treatment resistance in R/R PTCL patients remain unclear, despite therapeutic advances. Single-cell RNA sequencing was used to systematically characterize the transcriptional profiles of malignant T-cell clones and reactive T lymphocytes in seven tumor samples from six R/R PTCL patients to characterize the transcriptomic landscape of R/R PTCL and identify potential epigenetic biomarkers of drug response. We observed significant upregulation of genes associated with cell proliferation, oncogenic signaling, and immune modulation in R/R PTCL. Within the tumor microenvironment, we identified specific protumorigenic ligand–receptor interactions, including CXCL13–CXCR5, CCL5–CCR5, and CD74–MIF interactions, which may facilitate immune evasion by malignant T cells. Longitudinal data from a patient who progressed following dual epigenetic therapy revealed marked downregulation of immune response-related genes (HLA-DRA/DPA1/DRB5, CD74, C1QC, and LYZ) and functional reprogramming of tumor-associated macrophages. This study delineates the transcriptional heterogeneity of malignant T-cell clones in R/R PTCL and suggests its contribution to resistance to epigenetic therapies. These findings provide novel insights into the molecular mechanisms underlying treatment resistance and highlight potential avenues for therapeutic intervention in R/R PTCL.