Biomimetic Strategy Driven Deubiquitination for Enhanced Ferroptosis and Cancer Immunotherapy

Ubiquitination is the key mechanism that mediates protein stability and degradation, and the interference of ubiquitination is a promising approach to improve the therapeutic effects in cancer therapy. Here, we demonstrate that targeting inhibition of deubiquitinase OTUB1 could increase the ubiquitylation of PD-L1 and GPX4, which makes tumor cells vulnerable to the ferroptosis and immunotherapy. The therapeutic vehicles are designed through the encapsulation of metal-polyphenol network nanocomplexes (GA/Fe), doxorubicin (DOX), and siRNA targeting OTUB1 (siOTUB1) within a modified tumor cell membrane (SFD@M). Targeting delivery of SFD@M driven by tumor membrane efficiently decreases the expression of PD-L1 and GPX4 in tumor tissues. Without the protection of GPX4, GA/Fe complexes in SFD@M induce strong ferroptosis in tumor cells and initiate anti-tumor immune responses. Low expression of PD-L1 in tumor tissues due to excess ubiquitination maintain the activation of CD8+ T cells. In addition, the overexpression of PD-1 on edited tumor cell membrane regulates the function of Tregs and MDSCs, and further enhanced the anti-tumor effect of CD8+ T cells. SFD@M demonstrates efficient inhibition of tumor growth in orthotopic tumor models and cell line-derived xenograft (CDX) models in humanized NOG mice. This study employs the ubiquitination process in tumor cells to develop a biomimetic strategy that enhances ferroptosis and augments the immunotherapeutic efficacy in cancer treatment.