IL-16 production is a mechanism of resistance to BTK inhibitors and R-CHOP in lymphomas.

IL-16-driven signaling mediates resistance to BTK inhibitors and R-CHOP in B-cell lymphomas, with IL-16 upregulation observed in resistant cases.

• Why it matters: Overcoming resistance to BTK inhibitors remains a critical challenge in treating B-cell lymphomas, especially when resistance occurs without genetic mutations, limiting current therapeutic options.
• What they did: The study used chronic ibrutinib exposure to develop resistant models and employed multi-omics analyses to identify IL-16 as a key mediator, demonstrating its role in resistance across multiple lymphoma types.
• The result: Targeting the IL-16/CD9/PI3K pathway restored drug sensitivity, suggesting that disrupting this axis could improve outcomes in refractory B-cell lymphomas.