Overcoming chemoresistance: Restoring doxorubicin sensitivity and natural killer cell immunity in resistant DLBCL cells through reduction of endoplasmic reticulum stress

The recurrence of diffuse large B-cell lymphoma (DLBCL) is commonly attributed to its resistance to doxorubicin (DOX), which presents a significant therapeutic challenge and contributes to poor prognosis. Endoplasmic reticulum (ER) stress, pivotal in DOX resistance, is governed by regulating the survival of tumor cells and immune evasion. This study developed DOX-resistant DLBCL cell lines using murine xenografts to investigate the underlying mechanisms and potential therapeutic strategies. Comprehensive analyses were performed, focusing on stress-response pathways, oncogene-driven immunomodulatory signaling, and the cytotoxic activity of natural killer (NK) cells. Resistant cells exhibited elevated IRE1-XBP1s activation and c-MYC expression, which compromised NK cell-mediated tumor killing and reinforced immune evasion. Inhibition of XBP1s through ER stress inhibitor BI09 effectively dismantled this compensatory resistance strategy, reinstated NK cell sensitivity, and substantially increased tumor cell apoptosis. Notably, the combination of BI09 with DOX resulted in substantial anti-lymphoma activity at reduced DOX concentrations, thereby overcoming chemoresistance. These findings indicated that BI09 operated through a dual approach, simultaneously restoring chemosensitivity in refractory DLBCL and counteracting c-MYC-mediated immune evasion. Consequently, this study underscored the IRE1-XBP1s-c-MYC axis as a pivotal pathway in chemoresistance and immune suppression in DLBCL cells, and identified BI09 as a viable therapeutic candidate capable of disrupting chemoresistance and enhancing the efficacy of immunochemotherapy in aggressive lymphoma.