The objective of this study was to explore the effect of (-)-guaiol on lung cancer using experimental validation, mRNA sequencing, and network pharmacology. Potential targets of (-)-guaiol and lung cancer were identified through SwissTargetPrediction, TCMSP, PharmMapper, OMIM, GeneCards, and DisGeNET databases. Common targets were analyzed using PPI network, topological screening, and functional enrichment using STRING, Cytoscape, and Metascape. Molecular docking with core targets was performed, along with molecular dynamics. In vitro assays (cell counting kit-8 assay, colony formation, wound healing, Transwell, western blot) and in vivo studies (subcutaneous xenograft modeling in nude mice, immunohistochemistry, mRNA sequencing) were conducted to validate the anti-tumor effects and mechanisms of (-)-guaiol compared with the control group. Through multi-database prediction, 153 (-)-guaiol targets and 91 common lung cancer targets were identified. Protein-protein interaction (PPI) network analysis screened 21 core targets (including ESR1, EGFR, etc.). GO and KEGG enrichment analyses revealed that these targets are involved in the regulation of pathways such as fatty acid metabolism. Molecular docking and molecular dynamics results demonstrated that (-)-guaiol possessed a favorable binding affinity toward the target proteins SRC, PTGS2, GSK3B, PPARG, ESR1, and HSP90AA1. mRNA sequencing indicated that the gene expression levels of both PPARG and CD36 were downregulated in lung cancer tissues of mice treated with (-)-guaiol compared with the control group. Combining the results of molecular docking, molecular dynamics, and mRNA sequencing, we selected the PPARG-related signaling pathway for subsequent experiments. Both in vivo and in vitro experiments validated that (-)-guaiol inhibits lung cancer cell proliferation, invasion, and xenograft tumor growth in mice by downregulating the PPARG pathway. To conclude, our results demonstrated that (-)-guaiol suppresses lung cancer progression through downregulation of the fatty acid oxidation-related pathway mediated by PPARG.

Lung cancer is the leading cause of cancer-related deaths globally. Prolonged targeted therapy use can lead to drug resistance and target mismatches, necessitating more effective and safer treatment strategies. Recent research has focused on the tumor microenvironment, which includes immune and stromal cells that play roles in tumor proliferation, metastasis, and neovascularization. Tumor-associated macrophages (TAMs) are key immune cells in the tumor microenvironment, promoting tumor invasion, metastasis, and immune escape. Their infiltration density in lung cancer tissue is a poor prognostic factor. Piperlongumine (PL), extracted from Piper longum, possesses antitumor and anti-inflammatory properties, inducing apoptosis and inhibiting invasion and metastasis in lung cancer cells. This study aims to elucidate the correlation between endoplasmic reticulum stress (ERS) in lung cancer cells and M2-type TAM polarization and the role of PL in regulating lung cancer progression. The network pharmacologic analysis revealed that Piperlongumine inhibits lung cancer progression by inducing endoplasmic reticulum stress. In vivo experiments demonstrated that Piperlongumine significantly reduced tumor volume and decreased the proportion of M2-type macrophages. Within the co-culture system, lung cancer cells were shown to promote macrophage M2-type polarization and enhance cancer cell migration. Piperlongumine effectively inhibited these effects by inducing endoplasmic reticulum stress in cancer cells, thereby reducing M2 polarization and cell migration. The addition of endoplasmic reticulum stress inhibitor 4-PBA counteracted Piperlongumine’s effects, further underscoring the crucial role of ERS in the treatment mechanism. Piperlongumine suppresses lung cancer growth by inducing endoplasmic reticulum stress, which inhibits macrophage M2-type polarization and reduces cell migration. These findings support Piperlongumine’s potential as a therapeutic agent and offer a foundation for targeting endoplasmic reticulum stress to modulate TAM function in lung cancer treatment.

TME is a core player in the development of a cancerous lesion, the immune evasive potential of the lesion, and its response to therapy. Sphingolipid metabolism, which governs a number of cellular processes, has been recognised as a player involved in the control of immune heterogeneity within the TME. Sphingolipid metabolism-related genes prevalent in the TME of LUAD and LUSC were identified using transcriptomic analysis and clinical samples from the TCGA and GTEx databases. Lasso regression and survival SVM in the Etra Application were employed as machine learning algorithms to determine patient outcomes and to reveal key immune factors associated with gene expression and chemotherapeutic response. Gene expression in lung cancer cells was explored through scRNA-seq data. Thereafter, mediation impact analysis was further performed to explain the defined relation between the immune cell subsets and sphingolipid metabolites and their risk impact on lung cancers. Genes involved in sphingolipid metabolism were dysregulated in lung cancer, correlating with immune cell infiltration and TME remodelling. Lasso regression identified ASAH1 and SMPD1 as strong prognostic markers. scRNA-seq revealed higher gene expression in T cells, macrophages and fibroblasts. Sphingomyelin partially mediated the link between T lymphocyte abundance and lung cancer risk. High-risk phenotypes exhibited enhanced immune evasion via altered regulatory T cell and macrophage polarisation. This research highlights the contribution of sphingolipid metabolism in shaping the TME and its implications for immunotherapy.

M2 macrophages play a pivotal role in promoting the growth and metastasis of lung cancer cells. Inhibiting M2 macrophage polarization represents an effective immunotherapeutic approach against tumors. Although (-)-Guaiol has been shown to exert potent inhibitory effects on M2 macrophage polarization, its underlying molecular mechanism remains unclear. This study aimed to elucidate the effects of (-)-Guaiol on M2 macrophage polarization and to explore the potential molecular mechanisms involved. Bone marrow-derived macrophages (BMDMs) from mice were polarized toward the M2 phenotype using IL-4 and M-CSF. Both ex vivo and in vivo experiments were performed to determine whether (-)-Guaiol suppresses M2 macrophage polarization through the PPAR-γ-related signaling pathway. PPAR-γ agonists and inhibitors were applied to confirm the involvement of PPAR-γ in the effects of (-)-Guaiol. A co-culture system of M2 macrophages and Lewis lung carcinoma (LLC) cells was established. Wound healing, Transwell invasion, and plate cloning experiments were performed to determine the effects of (-)-Guaiol on the metastasis and development of lung cancer cells. (-)-Guaiol markedly downregulated the expression of CD206, a characteristic surface marker of M2-polarized macrophages. It also significantly inhibited the proliferation, invasion, and metastatic potential of LLC cells co-cultured with M2 macrophages. Animal experiments revealed that (-)-Guaiol treatment significantly decreased the tumor volume and weight, as well as CD206 expression. Moreover, integrated in vitro and in vivo analyses revealed that (-)-Guaiol inhibited M2 macrophage polarization primarily by suppressing the PPAR-γ signaling pathway. These findings demonstrate that (-)-Guaiol inhibits M2 macrophage differentiation via targeted suppression of the PPAR-γ-related signaling pathway, thereby reducing the proliferation, migration, and invasion of lung cancer cells.

Ursolic Acid (UA) is a naturally occurring pentacyclic triterpenoid compound that is prevalent in various medicinal plants and fruits. It has garnered significant attention due to its broad spectrum of anticancer properties. In this study, we evaluated the antitumor effects of UA on Non-Small Cell Lung Cancer (NSCLC).UA significantly inhibited NSCLC viability and induced cell death in a time- and dose-dependent manner. Furthermore, the administration of UA resulted in an elevation of intracellular reactive oxygen species (ROS), lipid ROS, and ferrous iron levels, while concurrently suppressing the expression of SLC7A11, glutathione, and GPX4. Consequently, this led to an augmentation in the concentration of the lipid peroxidation substrate, malondialdehyde. All the changes were effectively attenuated by the ferroptosis inhibitor Ferrostatin-1(Fer-1) and Deferoxamine (DFO). Moreover, similar observations were made in animal experiments. The sequencing data indicate that UA influences ferroptosis by modulating Fatty Acid Desaturase-2 (FADS2). The reintroduction of FADS2 through ectopic expression restored the resistance to ferroptosis induced by UA in A549 cells, while the addition of exogenous oleic acid (OA) counteracted the impact of UA on the oxidative response. These results suggest that UA induces ferroptosis in NSCLC by affecting redox pathways and the FADS2-mediated synthesis of unsaturated fatty acids.These studies collectively underscore the promising role of UA in the development of effective anticancer therapies.

Fu-Zheng-Qu-Xie (FZQX) decoction is a traditional Chinese herbal prescription for the treatment of lung cancer and exerts proapoptotic and immunomodulatory effects. It has been clinically suggested to be effective in improving the survival of postoperative early-stage lung adenocarcinoma (LUAD), but the mechanism remains unclear. In this study, we used network pharmacology coupled with metabolomics approaches to explore the pharmacological action and effective mechanism of FZQX against the recurrence and metastasis of postoperative early-stage LUAD. Network pharmacology analysis showed that FZQX could prevent the recurrence and metastasis of postoperative early-stage LUAD by regulating a series of targets involving vascular endothelial growth factor receptor 2, estrogen receptor 1, sarcoma gene, epidermal growth factor receptor, and protein kinase B and by influencing the Ras, PI3K-Akt, and mitogen-activated protein kinase signaling pathways. In liquid chromatography-mass spectrometry analysis, 11 differentially expressed metabolites, including PA(12:0/18:4(6Z,9Z,12Z,15Z)), PC(16:0/0:0)[U], LysoPC(18:1(11Z)), and LysoPC(18:0), were discovered in the FZQX-treated group compared to those in the model group before treatment or normal group. They were enriched in cancer metabolism-related signaling pathways such as central carbon metabolism in cancer, choline metabolism, and glycerol phospholipid metabolism. Collectively, our results suggest that the multicomponent and multitarget interaction network of FZQX inhibits the recurrence and metastasis of postoperative early-stage LUAD by activating the receptor signal transduction pathway to inhibit proliferation, induce cell apoptosis, inhibit aerobic glycolysis, and reprogram tumor lipid metabolism.

Lung cancer is a malignancy characterized by high morbidity and mortality, with lung adenocarcinoma being the most prevalent subtype. Our preliminary studies have demonstrated that the Juan-Liu-San-Jie (JLSJ) prescription, a Traditional Chinese Medicine prescription, possesses antilung adenocarcinoma cancer properties. However, the molecular mechanism underlying the therapeutic effects of the JLSJ prescription for lung adenocarcinoma remains incompletely elucidated. To address the knowledge gap, the present study employed network pharmacology to identify potential therapeutic targets. Specifically, the study utilized TCMSP, TCMID, and related references, as well as ChemMapper, to identify and predict the main active components and potential targets. Additionally, differentially expressed genes associated with the disease were obtained from the microarray dataset GSE19804 and GSE118370. The protein-protein Interaction network and Target-pathway network were then constructed. We also conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and subsequently presented the top 20 enriched pathways. The results indicated that the anti-lung cancer effects of JLSJ prescription may be attributed to its ability to mediate apoptosis of tumor cells, potentially through the PI3K/Akt signaling pathway. Then, a series of in vitro and in vivo experiments were conducted to validate the molecular mechanism predicted by network pharmacology. The findings of the in vivo study suggested that the JLSJ prescription could inhibit the growth of xenograft tumors of lung adenocarcinoma with fewer adverse effects. Also, the in vitro experiments corroborated that the JLSJ prescription could induce apoptosis of A549 cells. Furthermore, the upregulation of pro-apoptosis-related proteins and mRNAs, coupled with the downregulation of anti-apoptotic-related proteins and mRNAs, was observed. In conclusion, inducing apoptosis by inhibiting the PI3K/Akt signaling pathway was one of the underlying mechanisms by which the JLSJ prescription exerted its anti-lung adenocarcinoma effect.

综述肿瘤细胞代谢重编程的关键过程以及中医药调控肿瘤代谢重编程的研究进展.代谢重编程被认为是恶性肿瘤的标志特征.随着对肿瘤生物学复杂性的理解不断加深,医学界对肿瘤代谢重编程的研究也在不断加深.为满足细胞快速增殖的生物能量和生物合成需求,并快速适应肿瘤微环境,肿瘤细胞的能量代谢模式会相应进行重编程,主要体现在葡萄糖、脂质、氨基酸代谢的异常.中药具有多靶点、多途径、多通路调控的特点,可通过调控代谢重编程改变肿瘤细胞代谢微环境,进而发挥抗肿瘤作用.

Objective To investigate the effects and possible mechanism of Fuzheng Quxie Prescription on regulating DGKα-PA signaling axis on the proliferation and migration of human lung cancer H292 cells. Methods H292cells were divided into control group and Fuzheng Quxie Prescription low-, medium-and high-dosage groups. The Fuzheng Quxie Prescription low-, medium-and high-dosage groups were treated with 3, 6 and 12 mg/mL Fuzheng Quxie Prescription for 48 hours, and the control group was routinely cultured with an equal volume of medium.Proliferation of H292 cells were observed by colony formation assay; cell scratch test and Transwell assays were used to observe cell migration and invasion; ELISA was used to detect the content of phosphatidylic acid（PA） in H292cells; the protein expression of diacylglycerol kinase α（DGKα）, protein kinase B（AKT）, p-AKT and mechanistic target of rapamycin（mTOR） were detected by Western blot. Results Compared with the control group, the number of cell clones in the Fuzheng Quxie Prescription low-, medium-and high-dosage groups decreased significantly（P＜0.05, P＜0.01）, the cell migration rate significantly decreased（P＜0.01）, the number of invasive cells significantly decreased（P＜0.05, P＜0.01）, the content of PA in cells significantly reduced（P＜0.01）, the protein expressions of DGKα, p-AKT and mTOR significantly decreased（P＜0.05, P＜0.01）. The Fuzheng Quxie Prescription high-dosage group had the most obvious inhibitory effect（P＜0.01）. Conclusion Fuzheng Quxie Prescription can inhibit the proliferation and migration of human lung cancer H292 cells through the DGKα-PA signaling axis, and its mechanism may be related to the inhibition of downstream AKT/mTOR signaling pathway.

Tumor-associated macrophage (TAM)-mediated angiogenesis in the tumor microenvironment is a prerequisite for lung cancer growth and metastasis. Therefore, targeting TAMs, which block angiogenesis, is expected to be a breakthrough in controlling the growth and metastasis of lung cancer. In this study, we found that Sanguinarine (Sang) inhibits tumor growth and tumor angiogenesis of subcutaneously transplanted tumors in Lewis lung cancer mice. Furthermore, Sanguinarine inhibited the proliferation, migration, and lumen formation of HUVECs and the expression of CD31 and VEGF by regulating the polarization of M2 macrophages in vitro. However, the inhibitory effect of Sanguinarine on angiogenesis remained in vivo despite the clearance of macrophages using small molecule drugs. Further high-throughput sequencing suggested that WNT/β-Catenin signaling might represent the underlying mechanism of the beneficial effects of Sanguinarine. Finally, the β-Catenin activator SKL2001 antagonized the effect of Sanguinarine, indicating that Sanguinarine can regulate M2-mediated angiogenesis through the WNT/β-Catenin pathway. In conclusion, this study presents the first findings that Sanguinarine can function as a novel regulator of the WNT/β-Catenin pathway to modulate the M2 macrophage polarization and inhibit angiogenesis, which has potential application value in immunotherapy and antiangiogenic therapy for lung cancer.

BACKGROUND:Lung cancer is one of the most common causes of cancer-associated mortality worldwide. Upregulation of kinesin family member 15 (KIF15) expression has been observed in non-small cell lung cancer (NSCLC), and high expression levels of KIF15 are associated with a poor prognosis in patients with NSCLC. However, to the best of our knowledge, the mechanisms by which KIF15 regulates apoptosis, migration and invasion in NSCLC remain unclear.METHODS:Cell Counting Kit-8, flow cytometry and Transwell assays were performed to determine the proliferation, apoptosis and invasion of NSCLC cells, respectively. In addition, western blotting was used to detect the levels of phosphorylated (p-)c-Raf, p-ERK and p-MEK in NSCLC cells.RESULTS:Downregulation of KIF15 expression markedly inhibited the proliferation, migration and invasion of NSCLC cells through mediation of MMP2 and MMP9. In addition, downregulation of KIF15 markedly induced apoptosis and cell cycle arrest in NSCLC cells through regulation of active caspase 3, p27 Kip1 and cyclin D1. Furthermore, KIF15 knockdown notably decreased the levels of activating transcription factor 2, p-c-Raf, p-ERK and p-MEK in A549 and NCI-H460 cells. Finally, KIF15 knockdown notably inhibited the tumor growth of NSCLC in vivo.CONCLUSION:In conclusion, the present study indicated that downregulation of KIF15 expression was able to inhibit the tumorigenesis of NSCLC by inactivating Raf/MEK/ERK signaling. These findings may help improve the diagnosis and treatment of NSCLC.

目的:评价中药抗癌2号方联合高强度聚焦超声(HIFU)治疗中晚期胰腺癌的临床疗效及安全性.方法:将120例中晚期胰腺癌患者随机分为中药组、HIFU组和联合组,每组40例.所有患者均予基础治疗,中药组加予中药抗癌2号方口服,HIFU组加予HIFU治疗胰腺病灶,联合组加予中药抗癌2号方和HIFU治疗.比较3组患者的近期疗效、总生存期、临床获益反应、肿瘤标志物的变化情况,并监测不良反应.结果:联合组疾病控制率为78.4％(29/37),显著高于中药组的52.6％(20/38)(P＜0.05).与中药组及HIFU组比较,联合组在近期生存获益方面有显著优势(P＜0.05).联合组在体质量保持及疼痛程度缓解方面均优于HIFU组和中药组,临床获益显著,且有稳定肿瘤标志物的作用.3组患者血常规及肝肾功能均未出现显著的异常,治疗全程未见明显不良反应.结论:中药抗癌2号方联合HIFU可有效改善中晚期胰腺癌患者的临床症状,提升生活质量,并有助于提高患者生存率,疗效确切且安全性高.

Background: Accurately predicting the risk of recurrence in stage I-IIIA non-small cell lung cancer (NSCLC) after resection is critical in the treatment process. This study aimed to establish a novel nomogram to identify patients with a risk of disease progression in stage I-IIIA lung cancer based on clinical characteristics, peripheral T-lymphocyte subsets, and CD16+56 natural killer (NK) cells. Methods: A total of 306 NSCLC patients from Shanghai Municipal Hospital of Traditional Chinese Medicine between 2010 and 2020 who met the inclusion and exclusion criteria between January 2011 and December 2020 were retrospectively reviewed. Patients were randomly assigned to the training cohort (206 patients) and the validation cohort (100 patients). A nomogram model was developed based on the results of multivariate Cox regression in the training cohort. The optimal cut-off values were determined by X-tile software. The bootstrap method was used to validate the nomogram. Receiver operating characteristics curves (ROC) and the area under the ROC curve (AUC) were used to compare prognostic factors. The concordance index (C-index) was calculated to determine the accuracy of the nomogram in predicting disease-free survival (DFS). Results: Gender, drinking history, TNM stage, and CD4+T/CD8+T were independent factors for DFS and were integrated into the model, while CD16+56 NK cells were not proven to be significant independent factors for DFS. The calibration curves for probability of 3- and 5-year DFS showed excellent agreement between predicted and actual survival. The C-index for the nomogram to predict DFS was 0.839 in the training cohort. The nomogram showed an excellent predictive performance in the training cohort (3-/5-year AUC: 0.860/0.847) and in the validation cohort (3-/5-year AUC: 0.726/0.748). Conclusions: We developed a prognostic model which provided individual prediction of DFS for stage I-IIIA NSCLC patients after resection. This practical prognostic tool may help oncologists in clinical treatment planning.

目前,激活宿主抗肿瘤免疫应答的免疫治疗是肿瘤治疗领域的热点.但脂代谢重编程介导的微环境免疫抑制仍阻碍着肿瘤免疫治疗的进展.肿瘤细胞为满足自身快速增殖的需求而改变生物合成方式及代谢信号,其代谢产物可通过多种方式影响免疫细胞的激活及抗肿瘤免疫应答的发生.本文将从微环境条件下肿瘤脂代谢产物对免疫微环境的影响及治疗进展进行综述,以期为抗肿瘤治疗提供新的发展思路.

目的 基于均匀设计法筛选并验证蠲瘤散结方治疗肺腺癌的主效应药物或药物组合.方法 构建Lewis肺癌细胞皮下移植瘤模型,以蠲瘤散结方中6味药物(白英、夏枯草、海藻、石见穿、石上柏、牡蛎)为考察因素,选用U12(1210)均匀设计表,每因素6个水平,重复1次,按组方设计所得12种不同药物组合进行给药干预,以小鼠瘤体体积及瘤体质量为结局指标,通过建立回归方程筛选主效应药物或药物组合.对筛选所得主效应药物,再通过上述均匀设计方法及动物实验进行药效学验证,探索最佳剂量配比和核心效应药物.结果 筛选实验表明,与对照组比较,第10组小鼠瘤体体积和质量显著下降(P<0.05).逐步回归分析结果表明,白英+石见穿和石见穿+石上柏药物组合可显著降低小鼠瘤体负荷(P<0.05),3味药物是蠲瘤散结方发挥抗肺腺癌作用的主效应药物.验证实验结果表明,3味主效应药物不同配比与蠲瘤散结方抑瘤作用相当,最佳药物配比为白英:石见穿:石上柏=3:2:1.白英是蠲瘤散结方发挥抗肺腺癌作用的核心药物.结论 以白英为主的清热解毒药组是蠲瘤散结方发挥抑瘤作用的主效应药物,其抗肺腺癌疗效与蠲瘤散结方相当.

ObjectiveTo assess the expression of serum inflammatory cytokines and proportion of peripheral blood myeloid-derived suppressor cells (MDSCs) in patients with ground glass nodule (GGN) ≤1 cm in diameter and analyze clinical indicators that may affect the size and progression of pulmonary nodules and their clinical significance. MethodsThis prospective study included 111 patients with pulmonary GGNs ≤1 cm in diameter who were admitted to Shanghai Hospital of Traditional Chinese Medicine from April 2020 to July 2021. Based on pulmonary nodule size, 36 and 75 patients were divided into minute nodule (diameter <5 mm) and small nodule (diameter 5–10 mm) groups, respectively. The expression of inflammatory cytokines and proportion of MDSCs were determined, and the differences between the groups were analyzed. Follow-up visits were conducted every 6 months. The study endpoint was an increase in pulmonary GGN diameter of ≥2 mm or the occurrence of new GGNs. Risk factors that could affect the progression of pulmonary GGNs were also analyzed. ResultsThe proportion of MDSCs was higher in the small nodule group than in the minute nodule group, with the difference being significant (P<0.05). IL-2, IL-6, IL-8, and TNF-α expressions were not significantly different between the two groups (P>0.05). There was no significant difference in the change rate of pulmonary nodules between the two groups (P>0.05). The proportion of MDSCs was a risk factor that affected the progression of pulmonary GGNs, and the difference was statistically significant (P<0.05). Based on the cutoff proportion of MDSCs, the duration of stable disease stage was longer in the low-proportion MDSCs group (MDSCs <4.57%) than in the high-proportion MDSCs expression group (MDSCs≥4.57%), and the difference was statistically significant (P=0.001). ConclusionsThe proportion of MDSCs is correlated with the size of pulmonary GGNs, which may be one of the factors affecting the progression of pulmonary GGNs.

Ferroptosis, a type of iron-dependent oxidative cell death caused by excessive lipid peroxidation, is emerging as a promising cancer therapeutic strategy. Solasonine has been reported as a potential compound in tumor suppression, which is closely linked to ferroptosis. However, ferroptosis caused by solasonine is insufficiently identified and elaborated in lung adenocarcinoma, a fatal disease with high morbidity and mortality rates. First, the biochemical and morphological changes in Calu-1 and A549 cells exposed to solasonine are observed using a cell death assay and a microscope. The cell viability assay is performed after determining the executive concentration of solasonine to assess the effects of solasonine on tumor growth in Calu-1 and A549 cells. The ferroptosis is then identified by using ferroptosis-related reagents on CCK-8, lipid peroxidation assessment, Fe2+, and ROS detection. Furthermore, the antioxidant system, which includes GSH, Cys, GPx4, SLC7A11, and mitochondrial function, is measured to identify the potential pathways. According to the results, solasonine precisely exerts antitumor ability in lung adenocarcinoma cells. Ferroptosis is involved in the solasonine-induced cell death, as well as the accumulation of lipid peroxide, Fe2+, and ROS. Moreover, the failures of antioxidant defense and mitochondrial damage are considered to make a significant contribution to the occurrence of ferroptosis caused by solasonine. The study describes the potential process of ferroptosis caused by solasonine when dealing with lung adenocarcinoma. This encouraging evidence suggests that solasonine may be useful in the treatment of lung cancer.

近十年免疫疗法在肿瘤的治疗中取得了突破性进展,导致肿瘤治疗的范式转变.然而大多数患者并不能从中获益,如何提高患者免疫治疗的应答率是亟待解决的热点问题.免疫疗法的成功有赖于机体免疫效应细胞的活化及杀伤效应.然而,在肿瘤微环境严苛的代谢和营养应激下,免疫细胞的功能常处于紊乱状态,导致抗肿瘤免疫应答受损.因此,通过靶向肿瘤代谢重塑免疫微环境,恢复抗肿瘤免疫应答,有望在与免疫疗法的联合应用中取得协同效应.本文着重探讨代谢重编程及其代谢产物如何调节抗肿瘤免疫应答,旨在为肿瘤免疫治疗提供新的思路和方法.

Myeloid-derived suppressor cells (MDSCs) play an important role in the tumor-induced immunosuppressive microenvironment and have been linked with tumor development, proliferation, and resistance to treatment. Therefore, therapies that target MDSCs, such as sanguinarine (SNG), are now being considered potential treatments for lung cancer. However, the role of SNG in regulating the immune response in lung cancer is still not clear. In view of this, we evaluated the mechanism involved in the antitumor and immunoregulatory response to SNG therapy in a Lewis lung cancer (LLC) mouse model. The tumor mass and volume in the SNG treated LLC mouse model were significantly lower when compared with the control group (p < 0.05), indicating a good response to SNG. SNG also reduced the damage to the spleen, decreased the proportion of MDSCs, and increased the production of T helper 1 (Th1), T helper 2 (Th2), cytotoxic T-lymphocyte (CTL), macrophages, dendritic cells (DC) within the spleen. However, it did not affect the proportion of T helper 17 (Th17) and regulatory T cells (Treg). SNG also down-regulated the proportion of MDSCs in vitro and promoted their apoptosis, differentiation, and maturation. SNG was found to induce the differentiation of MDSCs into macrophages and DC through the nuclear factor kappa-B (NF-kappa B) pathway in vitro, while it also decreased the expression of arginase-1 (Arg-1) anti-inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS) in MDSCs.SNG also reduced the inhibitory effect on the proliferation of CD8+T cells. SNG may reduce the immunosuppressive state induced by lung cancer by promoting cell differentiation and by inhibiting the immunosuppressive activity of MDSCs.

BACKGROUND Lung adenocarcinoma (LUAD) is the most common type of lung cancer, which poses a serious threat to human life and health. -(-)Guaiol, an effective ingredient of many medicinal herbs, has been shown to have a high potential for tumor interference and suppression. However, knowledge of pharmacological mechanisms is still lacking adequate identification or interpretation. MATERIAL AND METHODS The genes of LUAD patients collected from TCGA were analyzed using limma and WGCNA. In addition, targets of (-)-Guaiol treating LUAD were selected through a prediction network. Venn analysis was then used to visualize the overlapping genes, which were further condensed using the PPI network. GO and KEGG analyses were performed sequentially, and the essential targets were evaluated and validated using molecular docking. In addition, cell-based verification, including the CCK-8 assay, cell death assessment, apoptosis analysis, and western blot, was performed to determine the mechanism of action of (-)-Guaiol. RESULTS The genes included 959 differentially-expressed genes, 6075 highly-correlated genes, and 480 drug-target genes. Through multivariate analysis, 23 hub genes were identified and functional enrichment analyses revealed that the PI3K/Akt signaling pathway was the most significant. Experiment results showed that -(-)Guaiol can inhibit LUAD cell growth and induce apoptosis. Additional evidence suggested that the PI3K/Akt signaling pathway established an inseparable role in the antitumor processes of -(-)Guaiol, which is consistent with network pharmacology results. CONCLUSIONS Our results show that the effect of (-)-Guaiol in LUAD treatment involves the PI3K/Akt signaling pathway, providing a useful reference and medicinal value in the treatment of LUAD.