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作者

Xiangyu Liu Xinyan Ju Ronghui Yuan Bingxue Pan Tongtong Feng Jingjing Ge Mengdi Wan Xiaoqian Li Fei Pan

作者单位

¹Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao 266000 Shandong, China ⁵Gynecology Department, Zouping City Center Hospital, Zouping 256200 Shandong, China ⁸Department of Medical Oncology, Sichuan Cancer Hospital & Institue, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041 Sichuan, China ¹⁰Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117 Shandong, China ⁶Phase I Clinical Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117 Shandong, China ⁹Department of Gastroenterology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117 Shandong, China ³Pediatric Oncology Ward, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117 Shandong, China ²Co-first authors: Xu-dong Li, Xin-yan Ju, Rong-hui Yuan, Bing-xue Pan, and Tong-tong Feng. ⁷Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060 Guangdong, China ⁴Cancer Center, Public Health Clinical Center Affiliated to Shandong University, Shandong Public Health Clinical Center, Jinan 250100 Shandong, China

刊名

Biochemical Pharmacology

年份

2025

页码

117395

ISSN

0006-2952

摘要

Triple-negative breast cancer is an aggressive phenotype of breast cancer with poor prognosis. Immunotherapy, including anti-programmed cell death protein 1 therapy, has shown promise in treating TNBC. This study investigates the impact of regulator of G protein signaling 1 on the efficacy of anti-PD-1 therapy in TNBC patients. Bioinformatics analyses were conducted to analyze differentially expressed genes in tissue-resident macrophages. Functional assays, including Transwell migration, co-c...更多

Triple-negative breast cancer is an aggressive phenotype of breast cancer with poor prognosis. Immunotherapy, including anti-programmed cell death protein 1 therapy, has shown promise in treating TNBC. This study investigates the impact of regulator of G protein signaling 1 on the efficacy of anti-PD-1 therapy in TNBC patients. Bioinformatics analyses were conducted to analyze differentially expressed genes in tissue-resident macrophages. Functional assays, including Transwell migration, co-culture experiments, quantitative polymerase chain reaction, and cytokine production, were conducted to evaluate the impact of RGS1 on macrophage function and CD8 T cell activity. Chromatin immunoprecipitation and luciferase assays were utilized to determine the regulatory mechanisms of RGS1 expression. RGS1 was upregulated in TNBC patients and specifically in tumor-associated macrophages . RGS1 knockdown in M2 macrophages reduced their chemotactic migration when co-cultured with cancer cells. In vivo, RGS1 knockdown in mice sensitized tumors to anti-PD-1 therapy, leading to reduced tumor growth and metastasis, elevated CD8 T cell infiltration, and prolonged survival. cAMP responsive element binding protein 1 and p300 were identified as key regulators of RGS1 expression, and their inhibition impaired M2 macrophage function, enhancing CD8 T cell activity. The effects of CREB1/p300 blockade were negated upon RGS1 overexpression. In conclusion, this study suggests that RGS1 is critical in maintaining the M2 phenotype of macrophage and reducing the efficacy of anti-PD-1 therapy in TNBC. Targeting RGS1 in TAMs may refine the efficacy of immune checkpoint blockade and improve clinical outcomes for TNBC patients. The regulatory mechanisms involving CREB1 and p300 offer potential therapeutic targets for modulating RGS1 expression and TAM function收起

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