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Inhibition of iRhom1 by CD44-targeting nanocarrier for improved cancer immunochemotherapy

Authors
  • Luo, Zhangyi
  • Huang, Yixian
  • Batra, Neelu
  • Chen, Yuang
  • Huang, Haozhe
  • Wang, Yifei
  • Zhang, Ziqian
  • Li, Shichen
  • Chen, Chien-Yu
  • Wang, Zehua
  • Sun, Jingjing
  • Wang, Qiming Jane
  • Yang, Da
  • Lu, Binfeng
  • Conway, James F
  • Li, Lu-Yuan
  • Yu, Ai-Ming
  • Li, Song
Publication Date
Jan 01, 2024
Source
eScholarship - University of California
Keywords
License
Unknown
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Abstract

The multifaceted chemo-immune resistance is the principal barrier to achieving cure in cancer patients. Identifying a target that is critically involved in chemo-immune-resistance represents an attractive strategy to improve cancer treatment. iRhom1 plays a role in cancer cell proliferation and its expression is negatively correlated with immune cell infiltration. Here we show that iRhom1 decreases chemotherapy sensitivity by regulating the MAPK14-HSP27 axis. In addition, iRhom1 inhibits the cytotoxic T-cell response by reducing the stability of ERAP1 protein and the ERAP1-mediated antigen processing and presentation. To facilitate the therapeutic translation of these findings, we develop a biodegradable nanocarrier that is effective in codelivery of iRhom pre-siRNA (pre-siiRhom) and chemotherapeutic drugs. This nanocarrier is effective in tumor targeting and penetration through both enhanced permeability and retention effect and CD44-mediated transcytosis in tumor endothelial cells as well as tumor cells. Inhibition of iRhom1 further facilitates tumor targeting and uptake through inhibition of CD44 cleavage. Co-delivery of pre-siiRhom and a chemotherapy agent leads to enhanced antitumor efficacy and activated tumor immune microenvironment in multiple cancer models in female mice. Targeting iRhom1 together with chemotherapy could represent a strategy to overcome chemo-immune resistance in cancer treatment.

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