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Background Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin’s lymphoma. Although standard immunochemotherapy is available, 30%–40% of patients develop refractory or relapsed disease, underscoring the need to elucidate the underlying mechanisms of therapy resistance. High mobility group box 2 (HMGB2) is overexpressed in DLBCL; however, its role in the pathogenesis of DLBCL and in mediating therapy resistance remains unclear.Methods HMGB2 expression and prognostic value in DLBCL were analyzed using public databases, validated by quantitative reverse transcription-PCR and western blot analysis. In vivo and in vitro HMGB2 knockdown models were constructed to explore its role in DLBCL. Macrophage-DLBCL co-culture systems were established to investigate HMGB2-mediated macrophage polarization. Transcriptome sequencing was performed to identify downstream targets of HMGB2, with molecular mechanisms confirmed by western blot analysis, co-immunoprecipitation, and immunofluorescence. Exosome isolation and protease protection assays were used to determine the HMGB2 secretion pathway.Results HMGB2 is overexpressed in DLBCL and correlates with poor prognosis. While HMGB2 knockdown showed no cell-intrinsic effects in vitro, it significantly suppressed tumor progression in vivo by remodeling the tumor microenvironment. We identified a novel mechanism whereby exosomal HMGB2 derived from DLBCL cells upregulates the E3 ubiquitin ligase tripartite motif containing 65 (TRIM65) in macrophages, promoting ubiquitin-mediated degradation of the NOD-like receptor protein 3 (NLRP3) inflammasome. This cascade drives M2-like macrophage polarization and impairs phagocytic function. Therapeutic targeting of this axis restored macrophage phagocytosis and synergized with CD20 immunotherapy to enhance its antitumor efficacy.Conclusion Our study defines the HMGB2-TRIM65-NLRP3 axis as a pivotal immunosuppressive pathway in DLBCL. Targeting this axis represents a promising combinatory strategy to reprogram the tumor microenvironment and overcome therapy resistance.