Abstract
The expression of CD30 in diffuse large B-cell lymphoma (DLBCL) has long been debated regarding its clinical significance. This report synthesizes the conflicting findings on CD30 and proposes a new paradigm. Central to this concept is that the prognostic value and biological function of CD30 are critically dependent on the lymphoma cell-of-origin (COO) and tumor microenvironment (TME) it shapes. Analysis of large-scale public gene expression datasets revealed that high CD30 expression is an independent favorable prognostic factor in DLBCL, but this effect is exclusively confined to the germinal center B-cell-like subtype. In contrast, CD30 expression showed no prognostic significance in the activated B-cell-like subtype. This specificity is attributable to CD30's role as a key architect of the TME, inducing an immune-tolerant environment, particularly through CD4+ T-cell infiltration and recruitment of regulatory T-cells. This understanding provides a strong rationale for COO- and TME-guided therapeutic strategies, such as combining the anti-CD30 antibody-drug conjugate brentuximab vedotin with immunomodulatory agents. This report elucidates the enigma of CD30 and outlines a path towards personalized medicine for DLBCL.