CUE domain-containing 2 promotes diffuse large B-cell lymphoma progression via PP2A-B55β degradation and shapes macrophage-mediated immune responses.

CUE domain-containing 2 (CUEDC2) regulates ubiquitin-mediated protein turnover, cell-cycle progression, and inflammatory signaling, but its role in diffuse large B-cell lymphoma (DLBCL) remains unclear. DLBCL is the most common aggressive non-Hodgkin lymphoma, and a substantial proportion of patients develop relapsed or refractory disease. Here, by integrating clinical bioinformatics, immunohistochemistry, and functional studies in DLBCL cell lines, we demonstrate that CUEDC2 is overexpressed in DLBCL and is associated with advanced disease stage and poor prognosis. Mechanistically, proteomic and ubiquitination analyses revealed that CUEDC2 interacts with the protein phosphatase 2A (PP2A) regulatory subunit B55 and promotes its ubiquitination-associated proteasomal degradation, accompanied by activation of NF-κB and mTOR signaling. Rescue studies support the role of PP2A-B55 as a downstream effector contributing to CUEDC2-associated proliferation and chemoresistance, and isoform-specific experiments identify PP2A-B55β as a preferentially regulated isoform. In addition, CUEDC2 knockdown in macrophages promoted M1-like polarization, enhanced phagocytosis, and supported CD8+ T cell activation and lymphoma cell apoptosis in vitro, without a detectable change in PP2A-B55 protein abundance. These immune effects were accompanied by changes in cellular metabolism and histone lactylation, although their causal relationships remain unresolved. Together, these findings support a tumor cell-intrinsic CUEDC2-PP2A-B55β-NF-κB/mTOR axis in DLBCL and suggest a potentially distinct immunomodulatory role for CUEDC2. Further mechanistic studies and in vivo validation are required to establish its therapeutic potential.