Advanced-stage cutaneous T-cell lymphoma (CTCL) is treated with diverse modalities, including DNA-damaging agents, anti-CD30 antibody-drug conjugates, and histone deacetylase (HDAC) inhibitors. Schlafen 11 (SLFN11) has emerged as a key determinant of sensitivity to DNA-damaging agents, yet its role in CTCL remains unclear. Here, we examined SLFN11 expression in two major CTCL subtypes-mycosis fungoides (MF) and Sézary syndrome (SS). Immunohistochemistry revealed SLFN11 positivity in 52% of MF (13/25) and 80% of SS (4/5) cases, with multivariate analysis showing a significant correlation between SLFN11 and CD30 expression. In normal human peripheral blood mononuclear cells, CD3/CD28/IL-2 stimulation induced co-expression of SLFN11 and CD30 in T cells, which was accompanied by heightened sensitivity to DNA-damaging agents. The JAK inhibitor cerdulatinib suppressed both markers. Among five CTCL cell lines, HUT78-expressing the highest SLFN11 levels-was the most sensitive to DNA-damaging agents, whereas SLFN11 knockout conferred resistance. Attempts to restore SLFN11 expression in SLFN11-low CTCL cells using six (pre)clinical HDAC inhibitors produced inconsistent results across cell lines and drugs. Together, these findings identify SLFN11 and CD30 as co-expressed therapeutic targets in CTCL and support the rationale for CD30-directed antibody-DNA-damaging agent conjugates as a precision treatment strategy.
© The Author(s) 2025. Published by Oxford University Press.