Increased ULBP1 by doxorubicin sensitizes neuroblastoma to γδT-cell cytotoxicity

Neuroblastoma (NB) is the most common extracranial solid tumor in children and remains a major therapeutic challenge in high-risk patients because of frequent recurrence and metastasis. γδT cells are a unique lymphocyte subset with potent antitumor activity and are widely distributed in NB tumors. However, the immunosuppressive tumor microenvironment limits γδT-cell effector function and promotes immune evasion. In this study, we found that ULBP1 expression was frequently down-regulated in NB tumor tissues and cell lines and that low ULBP1 expression was associated with high-risk clinical features and poor prognosis. Further investigation revealed that doxorubicin, a key chemotherapeutic agent used in NB treatment, up-regulated ULBP1 through down-regulating DNA methyltransferase 1 (DNMT1), thereby decreasing methylation of the ULBP1 promoter. This epigenetic modulation sensitized NB tumor cells to γδT-cell-mediated cytotoxicity in vitro and in vivo. Collectively, our findings uncover a novel mechanism by which doxorubicin enhances NB tumor susceptibility to γδT-cell-mediated killing through ULBP1 up-regulation. This study provides a strong rationale for combining chemotherapy with γδT-cell-based immunotherapy to improve outcomes in high-risk NB patients.