Exploring CAR-T Resistance Mechanisms in Relapsed/Refractory DLBCL via Integrated Histopathological and Transcriptomic Profiling.

In this hypothesis-generating study, we integrated histopathology and transcriptomics in six patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) receiving anti-CD19 CAR-T therapy, stratified into CAR-T-responsive and CAR-T-resistant cohorts by clinical response. Resistant tumors exhibited diffuse growth patterns with cohesive blast sheets, centroblastic morphology, tumor necrosis, and an immune-desert tumor microenvironment. Transcriptomics revealed three transcriptional programs that may correlate with CAR-T resistance: pro-fibrotic/extracellular matrix remodeling, proliferative and pro-survival traits, and immune dysfunction. Exploratory integrative analysis indicated associations between morphological features and pre-existing pathway dysregulation in CAR-T-resistant patients, such as hyperactivated PI3K-Akt-mTOR and impaired antigen presentation. Collectively, these observations imply CAR-T resistance in R/R DLBCL may stem from synergistic interplay among morphological aberrations, dysregulated proliferative/stromal pathways, and local immunosuppression. Pending prospective validation in larger independent cohorts, the candidate biomarkers observed herein may aid outcome prediction and combinatorial regimen design for R/R DLBCL.