Objective:This study aimed at exploring the effects of the epigenetic regulator,chidamide,on reprogramming the immunosuppressive tumor microenvironment in small cell lung cancer(SCLC),particularly the roles in macroph...Objective:This study aimed at exploring the effects of the epigenetic regulator,chidamide,on reprogramming the immunosuppressive tumor microenvironment in small cell lung cancer(SCLC),particularly the roles in macrophage polarization and angiogenesis.The therapeutic efficacy of combining chidamide with the anti-angiogenic agent,anlotinib,for refractory SCLC was also evaluated.Methods:RNA sequencing and functional validation were performed to assess chidamide’s effects on macrophages.Signal transducer and activator of transcription 4(STAT4)-mediated transcriptional activation of CCL2 was confirmed with ChIP-qPCR.The synergistic efficacy of chidamide in combination with anlotinib was tested in preclinical models.Results:Chidamide enhanced macrophage infiltration and induced macrophage polarization toward the anti-tumor M1 phenotype.Mechanistically,chidamide upregulated CCL2 via STAT4 transcriptional activation,thereby reshaping the tumor immune microenvironment(TIME).Combining chidamide with anlotinib synergistically suppressed tumor growth and remodeled the immunosuppressive TME in SCLC in vivo.Conclusions:Chidamide reshaped the SCLC TIME by activating STAT4/CCL2,thus driving M1 macrophage polarization and enhancing anti-tumor immunity.Our findings highlight coordinated TIME-targeted therapy as a translatable strategy to overcome therapeutic resistance in SCLC and provide a rationale for clinical trials examining epigenetic and anti-angiogenic therapeutics combinations.展开更多
Chronic pain,frequently comorbid with neuropsychiatric disorders,significantly impairs patients’quality of life and functional capacity.Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key...Chronic pain,frequently comorbid with neuropsychiatric disorders,significantly impairs patients’quality of life and functional capacity.Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key players in chronic pain pathogenesis.This review examines the regulatory mechanisms of the CCL2/CCR2 axis in chronic pain processing at three hierarchical levels:(1)Peripheral Sensitization:CCL2/CCR2 modulates TRPV1,Nav1.8,and HCN2 channels to increase neuronal excitability and CGRP signaling and calcium-dependent exocytosis in peripheral nociceptors to transmit pain.(2)Spinal Cord Central Sensitization:CCL2/CCR2 contributes to NMDAR-dependent plasticity,glial activation,GABAergic disinhibition,and opioid receptor desensitization.(3)Supraspinal Central Networks:CCL2/CCR2 signaling axis mediates the comorbidity mechanisms of pain with anxiety and cognitive impairment within brain regions,including the ACC,CeA,NAc,and hippocampus,and it also increases pain sensitization through the descending facilitation system.Current CCL2/CCR2-targeted therapeutic strategies and their development status are discussed,highlighting novel avenues for chronic pain management.展开更多
基金supported in part by grants from National Natural Science Foundation of China(Grant Nos.82172635,82272686,and 82203628)the Natural Science Foundation of Tianjin(Grant Nos.23JCZDJC00200 and 21JCYBJC01000)the Tianjin Key Medical Discipline(Specialty)Construction Project(Grant No.TJYXZDXK-010A).
文摘Objective:This study aimed at exploring the effects of the epigenetic regulator,chidamide,on reprogramming the immunosuppressive tumor microenvironment in small cell lung cancer(SCLC),particularly the roles in macrophage polarization and angiogenesis.The therapeutic efficacy of combining chidamide with the anti-angiogenic agent,anlotinib,for refractory SCLC was also evaluated.Methods:RNA sequencing and functional validation were performed to assess chidamide’s effects on macrophages.Signal transducer and activator of transcription 4(STAT4)-mediated transcriptional activation of CCL2 was confirmed with ChIP-qPCR.The synergistic efficacy of chidamide in combination with anlotinib was tested in preclinical models.Results:Chidamide enhanced macrophage infiltration and induced macrophage polarization toward the anti-tumor M1 phenotype.Mechanistically,chidamide upregulated CCL2 via STAT4 transcriptional activation,thereby reshaping the tumor immune microenvironment(TIME).Combining chidamide with anlotinib synergistically suppressed tumor growth and remodeled the immunosuppressive TME in SCLC in vivo.Conclusions:Chidamide reshaped the SCLC TIME by activating STAT4/CCL2,thus driving M1 macrophage polarization and enhancing anti-tumor immunity.Our findings highlight coordinated TIME-targeted therapy as a translatable strategy to overcome therapeutic resistance in SCLC and provide a rationale for clinical trials examining epigenetic and anti-angiogenic therapeutics combinations.
基金supported by grants from the Ministry of Science and Technology of China(2021ZD0203205 and 2021ZD0203104)the National Natural Science Foundation of China(82371225,82171212,82571386,82330036 and 82221001)+2 种基金National Key Research and Development Program of China(2024YFC2510102)the Excellent Youth Science Foundation of Shaanxi Province(2025JC-JCQN-103)Shaanxi Province Sanqin Talent Program.
文摘Chronic pain,frequently comorbid with neuropsychiatric disorders,significantly impairs patients’quality of life and functional capacity.Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key players in chronic pain pathogenesis.This review examines the regulatory mechanisms of the CCL2/CCR2 axis in chronic pain processing at three hierarchical levels:(1)Peripheral Sensitization:CCL2/CCR2 modulates TRPV1,Nav1.8,and HCN2 channels to increase neuronal excitability and CGRP signaling and calcium-dependent exocytosis in peripheral nociceptors to transmit pain.(2)Spinal Cord Central Sensitization:CCL2/CCR2 contributes to NMDAR-dependent plasticity,glial activation,GABAergic disinhibition,and opioid receptor desensitization.(3)Supraspinal Central Networks:CCL2/CCR2 signaling axis mediates the comorbidity mechanisms of pain with anxiety and cognitive impairment within brain regions,including the ACC,CeA,NAc,and hippocampus,and it also increases pain sensitization through the descending facilitation system.Current CCL2/CCR2-targeted therapeutic strategies and their development status are discussed,highlighting novel avenues for chronic pain management.
