3D ex vivo platform for high-throughput immunotherapy screening in relapsed/refractory lymphoma patients.

Relapsed/refractory (R/R) B-cell lymphomas (B-NHL) remain incurable, with limited predictive biomarkers to guide immunotherapy. Preclinical platforms that faithfully preserve the immune context and the viability of patient samples are critically needed for relevant high-throughput drug testing. Here, we present a 3D ex vivo platform for immunotherapy screening that generates patient-derived lymphoma spheroids (PDLS) a scaffold- and matrix-free 3D model derived from peripheral blood or lymph node biopsies of patients, including R/R follicular lymphoma, transformed follicular lymphoma, or diffuse large B-cell lymphoma. PDLS maintain the cellular composition, T-cell activation, and immune escape profiles of the original tumors, supporting multiplexed screening of single-agent and combination therapies within clinically relevant time frames. This scalable model recapitulates immune-tumor cell interactions, provides rapid assessment of immunotherapy efficacy, and bridges preclinical research with clinical application in aggressive B-cell lymphomas. By integrating spatial profiling and single-cell RNA sequencing, PDLS can further evolve into patient-specific 3D tumor avatars that support precision oncology approaches in aggressive B-NHL.