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

Zhangyi Luo, Yixian Huang, Neelu Batra, Yuang Chen, Haozhe Huang, Yifei Wang, Ziqian Zhang, Shichen Li, Chien-Yu Chen, Zehua Wang, Jingjing Sun, Qiming Jane Wang, Da Yang, Binfeng Lu, James F. Conway, Lu-Yuan Li, Ai-Ming Yu and Song Li ()
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Zhangyi Luo: University of Pittsburgh School of Pharmacy
Yixian Huang: University of Pittsburgh School of Pharmacy
Neelu Batra: University of California, Davis, School of Medicine
Yuang Chen: University of Pittsburgh School of Pharmacy
Haozhe Huang: University of Pittsburgh School of Pharmacy
Yifei Wang: University of Pittsburgh School of Pharmacy
Ziqian Zhang: University of Pittsburgh School of Pharmacy
Shichen Li: University of Pittsburgh School of Pharmacy
Chien-Yu Chen: University of Pittsburgh School of Pharmacy
Zehua Wang: University of Pittsburgh School of Pharmacy
Jingjing Sun: University of Pittsburgh School of Pharmacy
Qiming Jane Wang: University of Pittsburgh School of Medicine
Da Yang: University of Pittsburgh School of Pharmacy
Binfeng Lu: Hackensack Meridian Health
James F. Conway: University of Pittsburgh School of Medicine
Lu-Yuan Li: University of Pittsburgh
Ai-Ming Yu: University of California, Davis, School of Medicine
Song Li: University of Pittsburgh School of Pharmacy

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44572-6

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