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Inhibition of ARH2 by pH/ROS-responsive nanosystem for improved lung adenocarcinoma immunochemotherapy
Rui Cai1,2, Meng Wang1,2, Mengting Pan1,2
1Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China.
Abstract:
Immunotherapy resistance remains a substantial barrier to improving treatment outcomes for patients with lung adenocarcinoma (LUAD). Identifying effective immunotherapy target is crucial for enhancing therapeutic efficacy in LUAD. Through database analysis, we discovered that ADP ribosylhydrolase-like 1 (ADPRHL1, ARH2) is associated with immunosuppression. In this study, we first demonstrated that the increased presence of ARH2-positive macrophages in LUAD tumors is associated with immunosuppression. Furthermore, ARH2 promotes M2 macrophage polarization and suppresses immune responses by regulating the FPR2/PI3K/AKT signaling pathway. Additionally, we found that artesunate (ART) can induce necroptosis in LUAD cells and activate antitumor immune responses. To translate these findings into a clinically viable therapeutic approach, we developed a pH/ROS-responsive nanosystem capable of co-delivering siARH2 and ART. This nanosystem effectively activated immune responses in both tumor cells and tumor-associated macrophages. Furthermore, the nanosystem demonstrated excellent in vivo safety, precise PD-L1 targeting, and responsiveness to ROS and pH variations. It considerably suppressed the malignant phenotype of tumor cells induced by macrophages and enhanced T-cell-mediated immune responses. Overall, targeting ARH2 in combination with ART represents a promising novel strategy for the treatment of LUAD.
Insights
Targeting ADP ribosylhydrolase-like 1 (ARH2) and using artesunate (ART) shows promise for lung adenocarcinoma (LUAD) immunotherapy. A novel nanosystem co-delivers siARH2 and ART to activate anti-tumor immunity.
Area of Science:
- Oncology
- Immunology
- Nanotechnology
Background:
- Immunotherapy resistance is a major challenge in lung adenocarcinoma (LUAD) treatment.
- Identifying novel immunotherapy targets is crucial for improving therapeutic efficacy.
- ADP ribosylhydrolase-like 1 (ARH2) was identified as a potential factor associated with immunosuppression in LUAD.
Purpose of the Study:
- To investigate the role of ARH2 in LUAD-associated immunosuppression.
- To explore the potential of artesunate (ART) in combination with ARH2 targeting for LUAD treatment.
- To develop and evaluate a novel nanosystem for co-delivery of siARH2 and ART.
Main Methods:
- Database analysis to identify ARH2 association with immunosuppression.
- Assessment of ARH2-positive macrophages and their correlation with immunosuppression in LUAD.
- Investigation of ARH2's role in M2 macrophage polarization via the FPR2/PI3K/AKT pathway.
- Evaluation of artesunate (ART)-induced necroptosis and immune activation.
- Development of a pH/ROS-responsive nanosystem for co-delivery of siARH2 and ART.
- In vitro and in vivo assessment of the nanosystem's efficacy, safety, and targeting capabilities.
Main Results:
- Increased ARH2-positive macrophages in LUAD tumors correlate with immunosuppression.
- ARH2 promotes M2 macrophage polarization and suppresses immune responses through the FPR2/PI3K/AKT pathway.
- Artesunate (ART) induces necroptosis in LUAD cells and activates antitumor immunity.
- The developed nanosystem effectively co-delivered siARH2 and ART, activating immune responses in tumor cells and macrophages.
- The nanosystem demonstrated safety, PD-L1 targeting, and responsiveness to tumor microenvironment cues (pH/ROS).
- Co-delivery suppressed tumor cell malignancy and enhanced T-cell-mediated immunity.
Conclusions:
- Targeting ARH2 in combination with ART, delivered via a pH/ROS-responsive nanosystem, is a promising strategy for LUAD immunotherapy.
- This approach overcomes immunotherapy resistance by modulating macrophage polarization and enhancing anti-tumor immune responses.
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