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

[BACKGROUND] 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 5 (USP5) in regulating ferroptosis and immune evasion in DLBCL.

[METHODS] 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.

[RESULTS] 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.

[CONCLUSIONS] 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.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12964-025-02617-x.