Inhibition of ARH2 by pH/ROS-responsive nanosystem for improved lung adenocarcinoma immunochemotherapy
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-li...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
KeAi Communications Co., Ltd.
2025-11-01
|
| Series: | Bioactive Materials |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452199X25003354 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849389393084678144 |
|---|---|
| author | Rui Cai Meng Wang Mengting Pan Zhiwu Zhang Qiang Jia Longbao Feng Zhongjian Yu Lu Liu Tongyu Zhu Silin Cai Han Tian Jiangyu Zhang Rui Guo Yanfang Zheng |
| author_facet | Rui Cai Meng Wang Mengting Pan Zhiwu Zhang Qiang Jia Longbao Feng Zhongjian Yu Lu Liu Tongyu Zhu Silin Cai Han Tian Jiangyu Zhang Rui Guo Yanfang Zheng |
| author_sort | Rui Cai |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-93be76bf9b1940e6aa6f6ee150b58d89 |
| institution | Kabale University |
| issn | 2452-199X |
| language | English |
| publishDate | 2025-11-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Bioactive Materials |
| spelling | doaj-art-93be76bf9b1940e6aa6f6ee150b58d892025-08-20T03:41:58ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2025-11-015373775310.1016/j.bioactmat.2025.07.042Inhibition of ARH2 by pH/ROS-responsive nanosystem for improved lung adenocarcinoma immunochemotherapyRui Cai0Meng Wang1Mengting Pan2Zhiwu Zhang3Qiang Jia4Longbao Feng5Zhongjian Yu6Lu Liu7Tongyu Zhu8Silin Cai9Han Tian10Jiangyu Zhang11Rui Guo12Yanfang Zheng13Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China; State Key Laboratory of Respiratory Disease, Guangzhou, 510180, ChinaGuangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China; State Key Laboratory of Respiratory Disease, Guangzhou, 510180, ChinaGuangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China; State Key Laboratory of Respiratory Disease, Guangzhou, 510180, ChinaGuangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China; State Key Laboratory of Respiratory Disease, Guangzhou, 510180, ChinaGuangzhou City Polytechnic, Guangzhou, 510405, ChinaKey Laboratory of Biomaterials of Guangdong Higher Education Institutes, Guangdong Provincial Engineering and Technological Research Center for Drug Carrier Development, Department of Biomedical Engineering, Jinan University, Guangzhou, 510632, ChinaGuangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China; State Key Laboratory of Respiratory Disease, Guangzhou, 510180, ChinaGuangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China; State Key Laboratory of Respiratory Disease, Guangzhou, 510180, ChinaGuangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China; State Key Laboratory of Respiratory Disease, Guangzhou, 510180, ChinaGuangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China; State Key Laboratory of Respiratory Disease, Guangzhou, 510180, ChinaGuangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China; State Key Laboratory of Respiratory Disease, Guangzhou, 510180, ChinaGuangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China; Corresponding author.Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Guangdong Provincial Engineering and Technological Research Center for Drug Carrier Development, Department of Biomedical Engineering, Jinan University, Guangzhou, 510632, China; Corresponding author.Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China; State Key Laboratory of Respiratory Disease, Guangzhou, 510180, China; Corresponding author. Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China.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.http://www.sciencedirect.com/science/article/pii/S2452199X25003354ADP ribosylhydrolase-like 1 (ADPRHL1ARH2)Lung adenocarcinoma (LUAD)M2 macrophagesNecroptosispH/ROS-Responsive nanosystem |
| spellingShingle | Rui Cai Meng Wang Mengting Pan Zhiwu Zhang Qiang Jia Longbao Feng Zhongjian Yu Lu Liu Tongyu Zhu Silin Cai Han Tian Jiangyu Zhang Rui Guo Yanfang Zheng Inhibition of ARH2 by pH/ROS-responsive nanosystem for improved lung adenocarcinoma immunochemotherapy Bioactive Materials ADP ribosylhydrolase-like 1 (ADPRHL1 ARH2) Lung adenocarcinoma (LUAD) M2 macrophages Necroptosis pH/ROS-Responsive nanosystem |
| title | Inhibition of ARH2 by pH/ROS-responsive nanosystem for improved lung adenocarcinoma immunochemotherapy |
| title_full | Inhibition of ARH2 by pH/ROS-responsive nanosystem for improved lung adenocarcinoma immunochemotherapy |
| title_fullStr | Inhibition of ARH2 by pH/ROS-responsive nanosystem for improved lung adenocarcinoma immunochemotherapy |
| title_full_unstemmed | Inhibition of ARH2 by pH/ROS-responsive nanosystem for improved lung adenocarcinoma immunochemotherapy |
| title_short | Inhibition of ARH2 by pH/ROS-responsive nanosystem for improved lung adenocarcinoma immunochemotherapy |
| title_sort | inhibition of arh2 by ph ros responsive nanosystem for improved lung adenocarcinoma immunochemotherapy |
| topic | ADP ribosylhydrolase-like 1 (ADPRHL1 ARH2) Lung adenocarcinoma (LUAD) M2 macrophages Necroptosis pH/ROS-Responsive nanosystem |
| url | http://www.sciencedirect.com/science/article/pii/S2452199X25003354 |
| work_keys_str_mv | AT ruicai inhibitionofarh2byphrosresponsivenanosystemforimprovedlungadenocarcinomaimmunochemotherapy AT mengwang inhibitionofarh2byphrosresponsivenanosystemforimprovedlungadenocarcinomaimmunochemotherapy AT mengtingpan inhibitionofarh2byphrosresponsivenanosystemforimprovedlungadenocarcinomaimmunochemotherapy AT zhiwuzhang inhibitionofarh2byphrosresponsivenanosystemforimprovedlungadenocarcinomaimmunochemotherapy AT qiangjia inhibitionofarh2byphrosresponsivenanosystemforimprovedlungadenocarcinomaimmunochemotherapy AT longbaofeng inhibitionofarh2byphrosresponsivenanosystemforimprovedlungadenocarcinomaimmunochemotherapy AT zhongjianyu inhibitionofarh2byphrosresponsivenanosystemforimprovedlungadenocarcinomaimmunochemotherapy AT luliu inhibitionofarh2byphrosresponsivenanosystemforimprovedlungadenocarcinomaimmunochemotherapy AT tongyuzhu inhibitionofarh2byphrosresponsivenanosystemforimprovedlungadenocarcinomaimmunochemotherapy AT silincai inhibitionofarh2byphrosresponsivenanosystemforimprovedlungadenocarcinomaimmunochemotherapy AT hantian inhibitionofarh2byphrosresponsivenanosystemforimprovedlungadenocarcinomaimmunochemotherapy AT jiangyuzhang inhibitionofarh2byphrosresponsivenanosystemforimprovedlungadenocarcinomaimmunochemotherapy AT ruiguo inhibitionofarh2byphrosresponsivenanosystemforimprovedlungadenocarcinomaimmunochemotherapy AT yanfangzheng inhibitionofarh2byphrosresponsivenanosystemforimprovedlungadenocarcinomaimmunochemotherapy |