USP5 inhibition stimulates immunogenic ferroptosis that enhances immunotherapy in diffuse large B-cell lymphoma

Advances in immunotherapy have transformed the treatment landscape for diffuse large B-cell lymphoma (DLBCL), but drug resistance continues to limit its clinical efficacy. Ferroptosis, a form of immunogenic cell death, is critical for promoting adaptive anti-tumor immunity. Here, we report the role of ubiquitin specific peptidase (USP5) in regulating ferroptosis and immune evasion in DLBCL. The study employed in vitro and in vivo models of DLBCL to investigate the role of USP5 in ferroptosis and immune evasion. The main techniques included cell proliferation analysis, single-cell RNA sequencing, immunofluorescence, western blotting, microplate reader assays, and mouse xenograft models. The interaction between USP5 and insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) was confirmed through mass spectrometry, co-immunoprecipitation, and surface plasmon resonance, with further functional assessment conducted using rescue experiments. USP5 is highly expressed in DLBCL, and its deletion suppresses tumor growth in an immune system-dependent manner by enhancing the infiltration and activation of CD8+ T cells. Mechanistically, USP5 directly interacts with, deubiquitinates, and stabilizes IGF2BP3, thereby maintaining the mRNA stability of anti-ferroptotic factors and preventing ferroptosis and the release of damage-associated molecular patterns (DAMPs). Furthermore, USP5 inhibition significantly enhances the efficacy of anti-PD1 therapy via ferroptosis-mediated anti-tumor immunity in DLBCL mouse xenograft models. Collectively, our study reveals a critical role for the USP5-IGF2BP3 axis in suppressing immunogenic ferroptosis and provides a promising therapeutic target for DLBCL immunotherapy. USP5-mediated stabilization of IGF2BP3 via its deubiquitination activity impairs ferroptosis-driven anti-tumor immunity, positioning USP5 as a potential therapeutic target to enhance anti-PD1 therapeutic efficacy in DLBCL.