Although the first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone regimen (R-CHOP) substantially improved outcomes for patients with diffuse large B-cell lymphoma (DLBCL), 40% of the patients suffered from relapsed/refractory disease and had poor survival outcomes. The detailed mechanism underlying R-CHOP resistance has not been well defined. For this review, we conducted a thorough search for literature and clinical trials involving DLBCL resistance. We discussed DLBCL biology, epigenetics, and aberrant signaling of the B-cell receptor (
BCR
), phosphatidylinositol 3-kinase (
PI3K
)
/Akt
, nuclear factor kappa light chain enhancer of activated B-cells (
NF-κB
), and the Janus kinase (
JAK
)/signal transducer and activator of transcription 3 (
STAT3
) pathways as defining mechanisms of DLBCL heterogeneity and R-CHOP resistance. The cell of origin, double- or triple-hit lymphoma and double-protein-expression, clonal evolution, tumor microenvironment, and multi-drug resistance help to contextualize DLBCL resistance in an (epi)genetically and biologically comparative manner. With better understanding of the biological and molecular landscape of DLBCL, a more detailed classification system and tailored treatments will ideally become available to further improve the prognosis of DLBCL patients.
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