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Inhibition of iRhom1 by CD44-targeting nanocarrier for improved cancer immunochemotherapy
Zhangyi Luo1,2, Yixian Huang1,2, Neelu Batra3
1Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
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.
Insights
Targeting iRhom1 (inducible regulator of membrane trafficking 1) alongside chemotherapy can overcome chemo-immune resistance. This approach enhances chemotherapy sensitivity and boosts anti-tumor immune responses by modulating specific molecular pathways.
Area of Science:
- Oncology
- Immunology
- Nanotechnology
Background:
- Chemo-immune resistance is a major obstacle in cancer treatment.
- iRhom1 is implicated in cancer proliferation and negatively correlates with immune cell infiltration.
- Identifying novel targets is crucial for improving therapeutic outcomes.
Purpose of the Study:
- To investigate the role of iRhom1 in chemo-immune resistance.
- To explore iRhom1 as a therapeutic target for overcoming resistance.
- To develop a novel nanocarrier system for co-delivery of iRhom1 inhibition and chemotherapy.
Main Methods:
- Investigated iRhom1's role in regulating chemotherapy sensitivity via the MAPK14-HSP27 axis.
- Assessed iRhom1's impact on cytotoxic T-cell response by examining ERAP1 protein stability and antigen presentation.
- Developed and evaluated a biodegradable nanocarrier for co-delivery of iRhom1 pre-siRNA and chemotherapeutic agents.
- Utilized enhanced permeability and retention (EPR) effect and CD44-mediated transcytosis for tumor targeting and penetration.
Main Results:
- iRhom1 reduces chemotherapy sensitivity by regulating the MAPK14-HSP27 pathway.
- iRhom1 inhibits anti-tumor T-cell responses by destabilizing ERAP1 and impairing antigen presentation.
- The developed nanocarrier effectively targets tumors and penetrates tumor tissues.
- Inhibition of iRhom1 enhances nanocarrier-mediated tumor targeting and uptake.
- Co-delivery of iRhom1 pre-siRNA and chemotherapy significantly enhances anti-tumor efficacy and activates the tumor immune microenvironment in preclinical models.
Conclusions:
- iRhom1 is a critical regulator of chemo-immune resistance.
- Targeting iRhom1, in combination with chemotherapy, offers a promising strategy to overcome treatment resistance.
- The developed nanocarrier system provides an effective platform for co-delivering therapeutic agents to tumors.
- Combined targeting of iRhom1 and chemotherapy holds potential for improving cancer treatment outcomes.
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