Nature Communications (Jan 2024)

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,
  • Song Li

DOI
https://doi.org/10.1038/s41467-023-44572-6
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 20

Abstract

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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.