Targeting small ubiquitin‐related modifier‐specific protease 2 attenuates tumour progression and orchestrates the tumour immune microenvironment in diffuse large B‐cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive and heterogeneous haematological malignancy with poor outcomes, underscoring the need for novel therapeutic targets to improve remission rates. SUMO (small ubiquitin-related modifier)-specific protease 2 (SENP2) has been demonstrated to exert pleiotropic functions across diverse physiological processes and oncogenic transformation. Nevertheless, its precise function in DLBCL has rarely been investigated. Our research revealed that SENP2 was markedly overexpressed in DLBCL and its elevated levels were correlated with unfavourable prognosis. Furthermore, we constructed an integrative nomogram incorporating SENP2 expression and the International Prognostic Index score, which demonstrated robust predictive performance. Subsequently, SENP2 was validated to critically promote DLBCL cell proliferation both in vitro and in vivo. To investigate the underlying mechanisms, we performed RNA sequencing coupled with tumour infiltrating immune cells analysis, revealing that SENP2 knockout reduced myeloid-derived suppressor cell accumulation while simultaneously enhancing both the infiltration and functional activation of CD8⁺ T cells. Finally, we performed virtual screening of Food and Drug Administration-approved drugs against SENP2, followed by re-docking analysis and identified four of the most promising candidates. Collectively, our findings characterized SENP2 as a novel prognostic biomarker and a promising therapeutic target in DLBCL.