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. Overall design: 1.OTUB1 knockdown LLCs as well as its negative control were obtained through transfected with lenti-virus, which were further used to construct murine lung cancer orthotopic models, and RNAseq was performed to analyze the DEGs between OTUB1 knockdown murine lung cancer tissues and its negative control. 2.In order to gain a deeper understanding of the mechanism of SFD@M in cancer treatment. The mice were divided into blank group and SFD@M group. RNAseq was performed to investigate the changes in gene expression between the tumor tissues from Blank group and SFD@M group.