{"title":"靶向肿瘤相关巨噬细胞中CREB1/p300介导的RGS1表达可提高抗pd -1治疗三阴性乳腺癌的疗效。","authors":"Xiangyu Liu, Xinyan Ju, Ronghui Yuan, Bingxue Pan, Tongtong Feng, Jingjing Ge, Mengdi Wan, Xiaoqian Li, Fei Pan","doi":"10.1016/j.bcp.2025.117395","DOIUrl":null,"url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive phenotype of breast cancer with poor prognosis. Immunotherapy, including anti-programmed cell death protein 1 (anti-PD-1) therapy, has shown promise in treating TNBC. This study investigates the impact of regulator of G protein signaling 1 (RGS1) 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<sup>+</sup> 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 (TAMs). 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<sup>+</sup> T cell infiltration, and prolonged survival. cAMP responsive element binding protein 1 (CREB1) and p300 were identified as key regulators of RGS1 expression, and their inhibition impaired M2 macrophage function, enhancing CD8<sup>+</sup> 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.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117395"},"PeriodicalIF":5.6000,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeting CREB1/p300-mediated RGS1 expression in tumor-associated macrophages improves the efficacy of anti-PD-1 therapy in triple-negative breast cancer.\",\"authors\":\"Xiangyu Liu, Xinyan Ju, Ronghui Yuan, Bingxue Pan, Tongtong Feng, Jingjing Ge, Mengdi Wan, Xiaoqian Li, Fei Pan\",\"doi\":\"10.1016/j.bcp.2025.117395\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Triple-negative breast cancer (TNBC) is an aggressive phenotype of breast cancer with poor prognosis. Immunotherapy, including anti-programmed cell death protein 1 (anti-PD-1) therapy, has shown promise in treating TNBC. This study investigates the impact of regulator of G protein signaling 1 (RGS1) 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<sup>+</sup> 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 (TAMs). 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<sup>+</sup> T cell infiltration, and prolonged survival. cAMP responsive element binding protein 1 (CREB1) and p300 were identified as key regulators of RGS1 expression, and their inhibition impaired M2 macrophage function, enhancing CD8<sup>+</sup> 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.</p>\",\"PeriodicalId\":8806,\"journal\":{\"name\":\"Biochemical pharmacology\",\"volume\":\" \",\"pages\":\"117395\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2025-10-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochemical pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.bcp.2025.117395\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemical pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.bcp.2025.117395","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Targeting CREB1/p300-mediated RGS1 expression in tumor-associated macrophages improves the efficacy of anti-PD-1 therapy in triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is an aggressive phenotype of breast cancer with poor prognosis. Immunotherapy, including anti-programmed cell death protein 1 (anti-PD-1) therapy, has shown promise in treating TNBC. This study investigates the impact of regulator of G protein signaling 1 (RGS1) 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 (TAMs). 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 (CREB1) 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.
期刊介绍：
Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics.
The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process.
All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review.
While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.
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