A hypothetic model illustrating the pivotal role of CD37 status for R-CHOP outcome in DLBCL and the important molecular mechanisms for R-CHOP resistance in CD37⁻DLBCL and CD37⁺ABC-DLBCL. (A) Antiapoptotic and immune escape mechanisms existed in both CD37⁺ and CD37⁻ DLBCL before R-CHOP treatment. Comparably, CD37⁺ DLBCL had higher frequencies of ABC cell of origin and CXCR4 overexpression, whereas CD37⁻ DLBCL had higher frequencies of TP53 mutations and nuclear p50, STAT3, and Myc (only in GCB-DLBCL) overexpression. (B) CD37 positivity independently predicted favorable outcome, likely because CD37⁺ DLBCL is sensitive to R-CHOP owing to the increased CD20 and ICOSLG whereas decreased PD-1 expression (depicted by green 1, 3, and 2, respectively), as well as CD20-independent CD37 function in enhancing antibody-dependent cellular cytotoxicity (ADCC) and apoptosis upon CD20-rituximab ligation (*). This favorable impact can be hindered by ICOSLG and MHC-II downregulation, upregulation of PD-L1, AICDA, LILRA/B, IL10/IL10RA, and antiapoptotic pathways downstream of the chronic active BCR signaling in ABC-DLBCL. (C) CD37 loss robustly predicted poor survival. Rituximab efficacy is limited due to decreased CD20 levels (depicted by yellow 1, with postulated reasons of attenuated BCR, cytokine, and trogocytosis) and loss of CD37-rituximab signaling. The significantly worse prognosis is also contributed by 1 increased PD-1 (highlighted by yellow 2), ICOSLG downregulation (highlighted by yellow 3), and frequent TP53 mutations, Myc, STAT3, or p50 overexpression in CD37⁻ DLBCL (which were probably oncogenic drivers acquired during lymphomagenesis and further escaped from immune surveillance by various mechanisms as depicted). Illustrated immune escape mechanisms include upregulation of PD-L1/L2, LILRB/A, TIM3, CTLA4, and the IL6/IL10 pathway, and downregulation of MHC-I/II, CIITA, and costimulatory molecules CD58 and CD40. The model is based on our biomarker correlation, GEP, and survival analysis, except the speculated CD37 functions during R-CHOP treatment as denoted by an asterisk (*).