Single-cell characterization of 3D CLL spheroid model that recapitulates lymph node microenvironment-driven phenotypes and in vivo drug responses to ibrutinib

Single-cell profiling of paired peripheral blood and lymph node samples identifies three functional CLL states—resting, activated, and proliferating—with activated and proliferating subsets expanded in 3D spheroid cultures.

• Why it matters: Lymph node microenvironment signals are linked to CLL survival and treatment resistance, but how they reshape drug response across cellular states remains unclear.
• What they did: The study used single-cell RNA sequencing plus matched patient-derived CLL spheroids, then applied ibrutinib for 5 days and analyzed state shifts and pathway activity.
• The result: After 5 days of ibrutinib, CLL cells shifted toward a resting phenotype, and activated cells showed relative resistance linked to TLR9-MALT1-MYC pathway activation, supporting a physiologically relevant 3D platform.

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