Sensitization mechanism of Xiao'ai Jiedu Decoction in regulating macrophage polarization for PD-1 monoclonal antibody treatment of advanced non-small cell lung cancer
FANG Jinshu
HUANG Jianyi
ZHOU Shaorong
XU Xiao
PENG Juanjuan
LI Wenting
Abstract：Objective To investigate the sensitization mechanism of Xiao'ai Jiedu Decoction in regulating the polarization of tumor-associated macrophages(TAMs)for programmed death receptor-1(PD-1)monoclonal antibody treatment of advanced non-small cell lung cancer(NSCLC).Methods A mouse lewis lung carcinoma(LLC)tumor-bearing model was established by subcutaneously injecting 0.1 mL of LLC cell suspension into the right axilla.Forty tumor-bearing mice were randomly divided into four groups(n=10 per group):Model group,PD-1 monoclonal antibody group,Xiao'ai Jiedu Decoction group,and PD-1+Xiao'ai Jiedu Decoction group.The model group received intragastric administration of normal saline and intraperitoneal injection of phosphate-buffered solution.The PD-1 monoclonal antibody group received intragastric administration of sterile normal saline and intraperitoneal injection of PD-1 monoclonal antibody(200 μg/mouse).The Xiao'ai Jiedu Decoction group received intragastric administration of Xiao'ai Jiedu Decoction water decoction(15.75 g/kg/d of raw medicine)and intraperitoneal injection of phosphate-buffered solution.The PD-1+Xiao'ai Jiedu Decoction group received intragastric administration of Xiao'ai Jiedu Decoction water decoction and intraperitoneal injection of PD-1 monoclonal antibody(200 μg/mouse).The treatment lasted for 28 days.Tumor volume was measured on days 14,18,22,and 26 after intervention.Immunohistochemical staining was used to detect the enrichment of M2 macrophages in tumor tissues.Flow cytometry was employed to determine the proportion of TAMs subsets in tumor tissues.Western blot was used to measure the protein expression levels of phosphodiesterase 4D(PDE4D),protein kinase B(AKT),and p-AKT in tumor tissues.Results Compared with the model group,tumor volumes in the PD-1 monoclonal antibody group,Xiao'ai Jiedu Decoction group,and PD-1+Xiao'ai Jiedu Decoction group were reduced on days 14,18,22,and 26(P＜0.05).Compared with the PD-1 monoclonal antibody group and Xiao'ai Jiedu Decoction group,tumor volumes in the PD-1+Xiao'ai Jiedu Decoction group were further reduced on days 14,18,22,and 26(P＜0.05).Compared with the model group,the positive rates of macrophage mannose receptor(CD206),and the proportion of M2 macrophages in the PD-1 monoclonal antibody group,Xiao'ai Jiedu Decoction group,and PD-1+Xiao'ai Jiedu Decoction group were decreased(P＜0.05),while the proportion of M1 macrophages and the M1/M2 ratio were increased(P＜0.05).Compared with the PD-1 monoclonal antibody group and Xiao'ai Jiedu Decoction group,the PD-1+Xiao'ai Jiedu Decoction group showed lower positive rates of CD206(P＜0.05)and higher proportions of M1 macrophages and M1/M2 ratios(P＜0.05).Compared with the model group,the protein expression levels of PDE4D and the p-AKT/AKT ratio in the PD-1 monoclonal antibody group,Xiao'ai Jiedu Decoction group,and PD-1+Xiao'ai Jiedu Decoction group were decreased(P＜0.05).Compared with the PD-1 monoclonal antibody group and Xiao'ai Jiedu Decoction group,the PD-1+Xiao'ai Jiedu Decoction group exhibited lower PDE4D protein expression and p-AKT/AKT ratio(P＜0.05).Conclusions Xiao'ai Jiedu Decoction may regulate the polarization state of TAMs by inhibiting the PDE4D/AKT axis,promoting their transformation into the M1 phenotype and suppressing M2 polarization,thereby enhancing the anti-NSCLC efficacy of PD-1 monoclonal antibody.
Keywords：Non-small cell lung cancerXiao'ai Jiedu DecoctionMacrophagesSensitizationImmunoth-erapy
Publication Date：2025-12-20
Online Publishing Date：2026-01-13(First online date of this platform, not the publication date of the document)
Pages：7( 576-582 )