Ambient fine particulate matter (PM2.5) has been widely confirmed to severely threaten human health and is closely associated with the development and progression of respiratory diseases such as chronic obstructive pulmonary disease, pulmonary fibrosis, and lung cancer. This study aimed to investigate the key molecular targets and mechanisms by which PM2.5 induces lung cancer progression. Using an in vitro model, A549 cells were exposed to different concentrations of PM2.5 for 48 h. PM2.5 treatment significantly reduced cell proliferation, migration, and invasion, while increasing apoptosis. It also led to substantial reactive oxygen species (ROS) accumulation, impaired mitochondrial and lysosomal function, and abnormally enhanced autophagy. RNA-seq and RT-qPCR revealed that PM2.5 significantly upregulated cathepsin L (CTSL) expression, which correlated with the expression of autophagy-related genes p62/SQSTM1 and LC3B. Functional assays showed that CTSL overexpression further enhanced PM2.5-induced autophagic activity and promoted autophagic degradation, thereby promoting the malignant phenotype of A549 cells. Conversely, CTSL knockdown impaired autophagic degradation, reduced cell invasion, and aggravated cellular damage. These results suggest that PM2.5 promotes malignant transformation of A549 cells by upregulating CTSL and modulating autophagic homeostasis. In vivo experiments using an orthotopic mouse model confirmed the tumor-promoting role of CTSL and revealed that chronic PM2.5 exposure significantly promotes lung cancer growth within the tumor microenvironment. In conclusion, CTSL is a key molecular target in PM2.5-driven lung cancer progression. Targeting CTSL may offer new strategies for preventing and treating PM2.5-associated lung cancer and provide important theoretical insights into how environmental exposure factors drive tumor development.

Ethnopharmacological ImportanceSaorilao-4 (SRL-4) is a widely used Mongolian herbal formulation with reported therapeutic potential against pulmonary fibrosis (PF). The molecular mechanisms and key signaling pathways mediating its antifibrotic activity remain incompletely defined.Aim of studyTo determine how SRL-4 affects PF, with an emphasis on the epithelial–mesenchymal transition (EMT) and the PI3K/AKT/HIF-1α signaling pathway.Materials and methodsUHPLC-Q-Orbitrap high-resolution mass spectrometry was used to characterize the chemical composition of SRL-4. Network pharmacology analysis was applied to identify SRL-4–associated targets and enriched pathways relevant to PF. The five highest-degree targets and the five most influential active compounds within the protein–protein interaction network were selected for molecular docking analysis. PF was induced in mice through intratracheal bleomycin administration, followed by oral gavage of SRL-4 decoction starting one day after modeling and continuing for 28 days. PF severity and inflammatory responses were evaluated using lung coefficient analysis, histopathological staining, immunohistochemistry, and enzyme-linked immunosorbent assay. Western blotting was used to quantify EMT-associated proteins and important elements of the PI3K/AKT/HIF-1α pathway.ResultsUHPLC-Q-Orbitrap HRMS identified 189 chemical constituents in SRL-4. Network pharmacology analysis predicted 947 SRL-4–related targets and 8,597 PF-associated targets, with 705 overlapping genes. Functional enrichment profiling identified 724 Gene Ontology biological processes and 210 KEGG pathways associated with these shared molecular targets, spotlighting the PI3K/AKT/HIF-1α cascade as a critical regulatory axis. Molecular docking analyses examined five targets and five bioactive constituents with maximal Degree values from the protein-protein interaction network. Docking visualization emphasized binding interactions between AKT1, the leading hub target, and four key compounds exhibiting robust binding affinity. Histopathological assessment via hematoxylin–eosin staining, Masson's trichrome staining, and immunohistochemical profiling confirmed SRL-4's capacity to attenuate PF. ELISA and Western blot assays demonstrated that SRL-4 treatment lowered interleukin-6, interleukin-17, interleukin-1β, tumor necrosis factor-α, transforming growth factor-β, hydroxyproline, and hypoxia-inducible factor-1α concentrations, while augmenting E-cadherin and decreasing N-cadherin, α-smooth muscle actin, collagen I, collagen III, and vimentin. SRL-4 therapy further significantly suppressed p-PI3K, p-AKT, and HIF-1α protein levels. Integrated network pharmacology coupled with experimental verification revealed that SRL-4's anti-PF efficacy stems from EMT inhibition and PI3K/AKT/HIF-1α pathway modulation.ConclusionIntegrating network pharmacology, molecular docking, and experimental validation, this study confirms SRL-4's ability to inhibit EMT and suppress the PI3K/AKT/HIF-1α pathway, thereby exerting anti-fibrotic effects. These outcomes offer mechanistic evidence supporting the utilization of SRL-4 as a therapeutic intervention for pulmonary fibrosis management.

Identifying determinants of immune microenvironment remodeling in metastatic melanoma is critical for improving prognostic assessment and therapeutic stratification. In this study, we examined the expression and clinical significance of signal regulatory protein γ (SIRPG) in skin cutaneous melanoma (SKCM) through a combination of database mining, single-cell transcriptomics, and immunohistochemical (IHC) validation. SIRPG was significantly elevated in SKCM tissues compared with normal skin, and higher expression levels were associated with prolonged overall and disease-free survival. Functional and pathway analyses revealed that SIRPG was intimately linked to immune-related processes, and correlative analyses demonstrated strong associations between SIRPG expression and both immune cell infiltration and checkpoint molecule expression, with these associations being more pronounced in metastases than in primary tumors. Single-cell RNA sequencing further localized SIRPG expression predominantly to CD8+ exhausted T cells within metastatic lesions, and multiplex immunofluorescence confirmed enriched co-expression of SIRPG and PD-1 at the protein level. Taken together, these findings implicate SIRPG in the establishment of an exhaustion-prone immunosuppressive microenvironment in metastatic melanoma and highlight its potential utility as a biomarker for disease progression and immunotherapeutic response.

Crosstalk between gut microbiota and adipose tissue critically shapes immunotherapy responses in patients with cancer. An obesity-associated microbial signature enriched in riboflavin-producing taxa was identified, along with increased microbial riboflavin biosynthesis pathway and elevated levels of flavin adenine dinucleotide (FAD), in obese responders to immune checkpoint blockade (ICB). In diet-induced obese (DIO) mice, fecal microbiota transplantation (FMT), administration of Lachnospiraceae bacterium, or FAD supplementation significantly enhanced the therapeutic efficacy of anti-PD-1 therapy. These interventions increased the cytotoxicity of tumor-infiltrating CD8+ T cells via mesenteric adipocyte-driven synthesis of polyunsaturated fatty acids (PUFAs). Inhibiting fatty acid desaturase 2 (FADS2) eliminated the benefits of FAD, underscoring a critical role for adipocyte-intrinsic lipid remodeling in mediating immune responses. Clinically, elevated systemic levels of PUFAs, particularly docosahexaenoic acid (DHA), were positively correlated with intratumoral CD8+ T cell infiltration and favorable immunotherapy outcomes. Dietary DHA supplementation improved ICB responses in lean mice. This study highlights that a microbiota-adipose axis shapes antitumor immunity, enabling potential personalized metabolic and microbial immunotherapy strategies.

Lung cancer remains the leading cause of cancer-related mortality. The rising incidence among never-smokers underscores the role of environmental exposures, particularly contaminants of emerging concern (CECs) -a diverse group of largely unregulated chemicals with potential carcinogenicity. Yet, their links to lung cancer risk and prognosis are not well defined. To address this, we developed a robust and sensitive pseudo-targeted LC-MS/MS exposomics platform using 97 reference standards to semi-quantitatively profile 350 serum CECs in a hospital-based cohort comprising 570 lung cancer patients and 307 healthy controls. The method demonstrated high analytical reliability detecting 228 CECs across all participants. Several compounds-including monomethyl phthalate (MMPA), perfluorooctanesulfonic acid, and simazine-were significantly elevated in patients. Mixture models confirmed synergistic effects of co-exposures, and among 75 postoperative recurrence cases, MMPA, bisphenol G, and Irganox 245 emerged as. Key recurrence-associated chemicals. Absolute quantification revealed significantly higher serum MMPA levels in patients (83.09 μg/L) compared to controls (57.19 μg/L). Proteomic profiling of MMPA-exposed A549 lung cancer cells showed dysregulation in pathway related to chromatin remodeling, autophagy, cytochrome P450 metabolism, and immune function. This study integrates exposomics and proteomics to identify CECs linked to lung cancer development and recurrence, offering novel insights into environmental contributions and potential molecular targets in disease progression.

Identifying determinants of immune microenvironment remodeling in metastatic melanoma is critical for improving prognostic assessment and therapeutic stratification. In this study, we examined the expression and clinical significance of signal regulatory protein γ (SIRPG) in skin cutaneous melanoma (SKCM) through a combination of database mining, single-cell transcriptomics, and immunohistochemical (IHC) validation. SIRPG was significantly elevated in SKCM tissues compared with normal skin, and higher expression levels were associated with prolonged overall and disease-free survival. Functional and pathway analyses revealed that SIRPG was intimately linked to immune-related processes, and correlative analyses demonstrated strong associations between SIRPG expression and both immune cell infiltration and checkpoint molecule expression, with these associations being more pronounced in metastases than in primary tumors. Single-cell RNA sequencing further localized SIRPG expression predominantly to CD8+ exhausted T cells within metastatic lesions, and multiplex immunofluorescence confirmed enriched co-expression of SIRPG and programmed cell death protein 1 (PD-1) at the protein level. Taken together, these findings implicate SIRPG in the establishment of an exhaustion-prone immunosuppressive microenvironment in metastatic melanoma and highlight its potential utility as a biomarker for disease progression and immunotherapeutic response.

BACKGROUND:The aim of this study was to evaluate the short-term efficacy and safety of camrelizumab in combination with apatinib in the treatment of refractory or metastatic esophageal squamous cell carcinoma (ESCC). METHODS:We retrospectively reviewed the medical records of 30 patients with refractory or metastatic ESCC treated with camrelizumab in combination with apatinib at a single institution. The short-term efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria. The safety was evaluated by the Common Terminology Criteria for Adverse Events criteria. RESULTS:Among all the 30 patients, the overall response rate and disease control rate were 8/30 (27%) and 19/30 (63%), respectively. Complete response was achieved in 0/30 (0%), partial response in 8/30 (27%), stable disease in 11/30 (36%), and progressive disease in 11/30 (37%). The median progression-free survival was 3.7 (95% confidence interval: 2.48 - 3.88) months and the median overall survival was not reached. CONCLUSION:Our study has shown that camrelizumab in combination with apatinib is a promising therapy for patients with refractory or metastatic ESCC. This combination has a high response rate and favorable clinical safety.

Non-small cell lung cancer (NSCLC) is a prevalent form of lung cancer, primarily including adenocarcinomas and squamous cell carcinomas. Advances in targeted therapies have significantly improved NSCLC treatment. In this study, we developed a multifunctional fluorescent imaging nanodrug delivery system using fructose as a natural cross-linker due to its biocompatibility and low toxicity. The incorporation of zinc phthalocyanine-perfluorinated resin (ZnPc-PFR) into chitosan-fructose (CH-Fru) resulted in a nanocomposite with superior fluorescent properties and high loading capacity for compound 1, creating CH-Fru@ZnPc-PFR@1. Furthermore, the combination of compound 1 and gefitinib formed the CH-Fru@ZnPc-PFR@1@Gefitinib composite system, which demonstrated a synergistic effect in inhibiting NSCLC cell proliferation. This study not only developed an effective nanodrug delivery system but also highlighted the potential therapeutic benefits of combining compound 1 with gefitinib for lung cancer treatment.

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment but remains effective in only a subset of patients. Emerging evidence suggests that the gut microbiome and its metabolites critically influence ICB efficacy. In this study, we performed a multi-omics analysis of fecal microbiomes and metabolomes from 165 patients undergoing anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) therapy, identifying microbial and metabolic entities associated with treatment response. Integration of data from four public metagenomic datasets (n = 568) uncovered cross-cohort microbial and metabolic signatures, validated in an independent cohort (n = 138). An integrated predictive model incorporating these features demonstrated robust performance. Notably, we characterized five response-associated enterotypes, each linked to specific bacterial taxa and metabolites. Among these, the metabolite phenylacetylglutamine (PAGln) was negatively correlated with response and shown to attenuate anti-PD-1 efficacy in vivo. This study sheds light on the interplay among the gut microbiome, the gut metabolome, and immunotherapy response, identifying potential biomarkers to improve treatment outcomes.

Lactate metabolism (LM) plays a crucial role in tumor progression and therapy resistance in non-small cell lung cancer (NSCLC). Several methods had been developed for NSCLC prognosis prediction based on lactate metabolism-related information. The existing methods for the construction of prognosis prediction models are mostly based on single models such as linear models, SVM, and decision trees. Prognosis biomarkers and prognosis prediction models based on this kind of methods often have limited prognostic performance. In this study, we proposed a novel methodology for constructing prognosis prediction model and identifying lactate-related prognostic biomarkers in NSCLC. We first screened for lactate metabolism-related malignant genes from the scRNA-Seq data of NSCLC malignant cells. We proposed a Cox elastic-net regression combined with genetic algorithm (GA-EnCox) to predict prognosis and optimize the selection of key biomarkers. We identified five key LM-related genes (LYPD3, KRT8, CCT6A, PSMB7, and HMGA1) that significantly correlated with patient prognosis in LUAD cohorts. The prognostic model constructed with these genes outperformed other currently popular models across multiple datasets, demonstrating stable predictive capability. Survival analysis based on bulk RNA-Seq data demonstrated that the low-risk group had significantly better overall survival compared to the high-risk group. Further analysis revealed that lactate metabolism-related prognosis risk might be associated with monocyte lineages such as macrophages and DC’s infiltration and these prognosis biomarkers may indicate the therapeutic responses of immune checkpoint inhibitors for NSCLC patients. More importantly, we validated HMGA1 and KRT8 at protein level and their association with histologic grades, stages, and clinical outcomes in consistently treated in-house NSCLC cohorts. Finally, we experimentally validated one of the biomarkers, HMGA1, confirming its role in promoting malignant phenotypes of NSCLC. This study provides valuable insights into the role of lactate metabolism-related biomarkers and their impact on patient outcomes, it was expected to provide important reference value for prognosis assessment and personalized treatment decision of NSCLC patients.

Immunotherapy has revolutionized cancer treatment, but response variability remains a challenge. The gut microbiome's role in therapeutic efficacy is well established, but the impact of the gut mycobiome is less understood. Using unsupervised clustering, we identify two gut mycobiome-based enterotypes, favorable type and unfavorable type, characterized by distinct microbial compositions linked to immunotherapy outcomes. Favorable-type enterotypes exhibit higher fungal and bacterial alpha diversity, enriched butyrate-producing bacteria, and metabolic pathways related to butyric acid and sugar/starch metabolism. External validation confirms their predictive value in assessing immunotherapy efficacy. Multi-omics analysis reveals increased CD8+ T cell infiltration in the tumor microenvironment of favorable-type patients. Fecal microbiota transplantation (FMT) from favorable-type donors enhances anti-PD-1 sensitivity, promotes CD8+ T cell infiltration, and boosts butyrate production in vivo. These findings highlight the gut mycobiome's role in immunotherapy response and support FMT from favorable-type donors as a potential strategy for improving treatment outcomes and patient stratification.

Cisplatin (DDP) resistance substantially compromises treatment efficacy in lung adenocarcinoma (LUAD). This study investigates the role of mitochondrial long non-coding RNA (lncRNA) H19 in mediating DDP resistance. High-throughput sequencing and RT-qPCR analyses revealed pronounced H19 upregulation in DDP-resistant A549 (A549/DDP) cells relative to parental A549 cells. Subcellular localization studies indicated that H19 is primarily nuclear in A549 cells but translocates to mitochondria in A549/DDP cells. Functional assays demonstrated that H19 silencing in resistant cells attenuated chemoresistance, suppressed proliferation, migration, invasion, and colony formation in vitro, and delayed tumor growth in vivo. H19 knockdown impaired mitophagy and promoted apoptosis, mirroring autophagy inhibition and restoring DDP sensitivity. In contrast, H19 overexpression in A549 cells did not significantly alter mitophagy or cellular behavior. Furthermore, H19 silencing induced its relocalization from mitochondria back to the nucleus in resistant cells, while overexpression did not affect its nuclear localization. These findings establish that H19 translocation to mitochondria promotes DDP resistance, and its downregulation reverses this process by inhibiting mitophagy and resensitizing cells to DDP. As a nucleus-encoded mitochondria-associated lncRNA (ntmtlncRNA), H19 mediates intercompartmental communication, highlighting its potential as a therapeutic target for overcoming DDP resistance in LUAD.

WNK lysine deficient protein kinase 4 (WNK4) has been shown to be significantly associated with cancer progression. Nevertheless, its involvement in gastric cancer (GC) is unclear. The objective of this work was to investigate the WNK4's regulatory mechanism in GC. Quantitative RT-PCR and immunoblots revealed that WNK4 expression was downregulated in GC and that low expression of WNK4 was strongly linked to poor prognosis. Functional assays including cell counting kit-8 assay and colony formation assay demonstrated that overexpression of WNK4 led to limited tumor proliferation both in vitro and in vivo, while the WNK4 reduction yielded to the opposite results. Gene Set Enrichment Analysis (GSEA) indicated a potential association between WNK4 and the signal transducer and activator of transcription (STAT3). WNK4 suppressed the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) in GC cells. The inhibition of the STAT3 pathway with Stattic reversed growth and proliferation induced by WNK4 knockdown in GC cells. These findings provide new insights for identifying key therapeutic targets for GC in the future.

Background The impact of the gut microbiome on the initiation and intensity of immune-related adverse events (irAEs) prompted by immune checkpoint inhibitors (ICIs) is widely acknowledged. Nevertheless, there is inconsistency in the gut microbial associations with irAEs reported across various studies. Methods We performed a comprehensive analysis leveraging a dataset that included published microbiome data ( n = 317) and in-house generated data from 16S rRNA and shotgun metagenome samples of irAEs ( n = 115). We utilized a machine learning-based approach, specifically the Random Forest (RF) algorithm, to construct a microbiome-based classifier capable of distinguishing between non-irAEs and irAEs. Additionally, we conducted a comprehensive analysis, integrating transcriptome and metagenome profiling, to explore potential underlying mechanisms. Results We identified specific microbial species capable of distinguishing between patients experiencing irAEs and non-irAEs. The RF classifier, developed using 14 microbial features, demonstrated robust discriminatory power between non-irAEs and irAEs (AUC = 0.88). Moreover, the predictive score from our classifier exhibited significant discriminative capability for identifying non-irAEs in two independent cohorts. Our functional analysis revealed that the altered microbiome in non-irAEs was characterized by an increased menaquinone biosynthesis, accompanied by elevated expression of rate-limiting enzymes menH and menC . Targeted metabolomics analysis further highlighted a notably higher abundance of menaquinone in the serum of patients who did not develop irAEs compared to the irAEs group. Conclusions Our study underscores the potential of microbial biomarkers for predicting the onset of irAEs and highlights menaquinone, a metabolite derived from the microbiome community, as a possible selective therapeutic agent for modulating the occurrence of irAEs.

Immunotherapy has revolutionized cancer treatment, but inconsistent responses persist. Our study delves into the intriguing phenomenon of enhanced immunotherapy sensitivity in older individuals with cancers. Through a meta-analysis encompassing 25 small-to-mid-sized trials of immune checkpoint blockade (ICB), we demonstrate that older individuals exhibit heightened responsiveness to ICB therapy. To understand the underlying mechanism, we reanalyze single-cell RNA sequencing (scRNA-seq) data from multiple studies and unveil distinct upregulation of exhausted and cytotoxic T cell markers within the tumor microenvironment (TME) of older patients. Recognizing the potential role of gut microbiota in modulating the efficacy of immunotherapy, we identify an aging-enriched enterotype linked to improved immunotherapy outcomes in older patients. Fecal microbiota transplantation experiments in mice confirm the therapeutic potential of the aging-enriched enterotype, enhancing treatment sensitivity and reshaping the TME. Our discoveries confront the prevailing paradox and provide encouraging paths for tailoring cancer immunotherapy strategies according to an individual's gut microbiome profile.

目的 探讨单羧酸转运蛋白(MCT)在胃癌的表达及临床意义.方法 选取 2018 年 1 月—2020 年 12月徐州市中心医院收治的病理学诊断为胃腺癌的患者 56 例.收集其胃癌组织及其配对的癌旁正常组织标本、正电子发射计算机断层成像(PET/CT)结果.采用GEPIA2 和kmplot数据库分析MCT1-4 在胃癌组织的表达及其与胃癌疾病分期和预后的相关性.采用免疫组化法检测MCT4、葡萄糖转运蛋白(GLUT1)及缺氧诱导因子(HIF)-1α 的表达.采用GEPIA2 在线分析MCT4 表达与GLUT1 和HIF-1 的关系.结果 GEPIA2 分析显示,MCT1 和MCT4 基因表达在胃癌组织较非肿瘤组织显著增高(P<0.05),而MCT2 和MCT3 的基因表达差异无统计学意义(P>0.05);MCT1 和MCT4 基因与胃癌分期相关性差异无统计学意义(P>0.05).kmplot数据库显示MCT1 mR-NA高表达患者总生存期(OS)增加(P<0.001),MCT4 mRNA高表达患者OS减少(P<0.001).此外,MCT4 蛋白表达在胃癌组织较正常组织明显升高(P=0.0006).GEPIA2 分析和免疫组化染色结果提示MCT4 表达与葡萄糖转运蛋白(GLUT1)和缺氧诱导因子(HIF-1)的表达呈正相关.结论 MCT4 参与调控GC糖代谢的重编程和肿瘤微环境,与GC的发生发展密切相关,可作为潜在的预后标志物,有可能作为GC患者的候选治疗靶点.

Objective: Circular RNAs (circRNAs) have been shown to participate in various cancers via sponging miRNAs (microRNAs). However, their role in lung adenocarcinoma (LUAD) remains elusive.Methods: The transcriptome data and corresponding clinical information of lung adenocarcinoma samples were extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Differentially expressed circRNAs (DEcircRNAs), differentially expressed miRNAs (DEmiRNAs), and differentially expressed genes (DEgenes) were identified and further used to constructed a circRNA-associated competing endogenous RNA (ceRNA) network. Real-Time qPCR analysis was conducted to examine gene expression at transcriptional level. The regulatory mechanisms of circRNA-miRNA-gene were validated by dual-luciferase reporter array and RNA pull-down assay. Cell growth, migration and invasion were evaluated by CCK-8 assay, colony formation assay and transwell assay, respectively.Results: Based on public microarray data, we systematically constructed a circRNA-associated ceRNA network including 11 DEcircRNAs, 8 DEmiRNAs and 49 DEgenes. Among the ceRNA network, we found that circ-0002727 was a key regulatory and was further confirmed to be upregulated in LUAD cancer cells. Subsequently, we found that silencing of circ-0002727 significantly suppressed the LUAD cell proliferation, migration and invasion in vitro. Mechanistically, we showed that circ-0002727 could competitively bind miR-144-3p to enhance the KIF14 expression in LUAD cells. Rescue assays indicated that circ-0002727 could regulate LUAD cell proliferation through modulating miR-144-3p/KIF14 pathway. Besides, KIF14 expression level was positively correlated with TNM stage and metastasis, and patients with high KIF14 expression suffered poor prognosis.Conclusion: Taken together, our study revealed that circ-0002727 could act as a ceRNA to regulate LUAD progression via modulating miR-144-3p/KIF14 pathway, providing a potential therapeutic target for LUAD.

The perturbations of the gut microbiota and metabolites are closely associated with the progression of inflammatory bowel disease (IBD). However, inconsistent findings across studies impede a comprehensive understanding of their roles in IBD and their potential as reliable diagnostic biomarkers. To address this challenge, here we comprehensively analyze 9 metagenomic and 4 metabolomics cohorts of IBD from different populations. Through cross-cohort integrative analysis (CCIA), we identify a consistent characteristic of commensal gut microbiota. Especially, three bacteria, namely Asaccharobacter celatus , Gemmiger formicilis , and Erysipelatoclostridium ramosum , which are rarely reported in IBD. Metagenomic functional analysis reveals that essential gene of Two-component system pathway, linked to fecal calprotectin, are implicated in IBD. Metabolomics analysis shows 36 identified metabolites with significant differences, while the roles of these metabolites in IBD are still unknown. To further elucidate the relationship between gut microbiota and metabolites, we construct multi-omics biological correlation (MOBC) maps, which highlights gut microbial biotransformation deficiencies and significant alterations in aminoacyl-tRNA synthetases. Finally, we identify multi-omics biomarkers for IBD diagnosis, validated across multiple global cohorts (AUROC values ranging from 0.92 to 0.98). Our results offer valuable insights and a significant resource for developing mechanistic hypotheses on host-microbiome interactions in IBD.

The effect of gut bacteria on the response to immune checkpoint inhibitors (ICIs) has been studied, but the relationship between fungi and ICI responses is not fully understood. Herein, 862 fecal metagenomes from 9 different cohorts were integrated for the identification of differentially abundant fungi and subsequent construction of random forest (RF) models to predict ICI responses. Fungal markers demonstrate excellent performance, with an average area under the curve (AUC) of 0.87. Their performance improves even further, reaching an average AUC of 0.89 when combined with bacterial markers. Higher enrichment of exhausted T cells is detected in responders, as predicted by fungal markers. Multi-kingdom network and functional analysis reveal that the fungus Schizosaccharomyces octosporus may ferment starch into short-chain fatty acids in responders. This study provides a fungal profile of the ICI response and the identification of multi -kingdom microbial markers with good performance that may improve the overall applicability of ICI therapy.

目的 本研究旨在探讨SMAD7、SMAD9 在肺腺癌中的预后价值及其与免疫浸润的相关性.方法 借助GEPIA数据库预测SMAD家族成员在肺腺癌组织与癌旁组织中的表达水平,筛选差异表达的成员作为关键基因纳入研究.分析关键基因对肺腺癌患者预后的影响,GEPIA与TIMER数据库分析关键基因与免疫浸润的相关性.收集 108 例手术切除的肺腺癌患者组织,使用qRT-PCR验证关键基因在组织内的表达水平.分析关键基因对患者 5 年生存率的影响及影响生存率的独立预测因素.结果 GEPIA 数据库预测结果显示,相对于正常组织样本,SMAD7、SMAD9 在癌组织样本中的表达降低(P 均<0.05).GEPIA 数据库预测结果显示 SMAD7、SMAD9 低表达水平患者总生存率低于 SMAD7、SMAD9 高表达水平患者(P 均<0.05).TIM-ER网站预测结果显示SMAD7 与B细胞、CD4+ T 细胞、巨噬细胞、中性粒细胞、树突状细胞水平均呈正相关(P 均<0.05),SMAD9 与 B 细胞、CD4+ T 细胞、巨噬细胞水平呈正相关(P 均<0.05).GEPIA网站显示SMAD7 与CD115、CD86、CD68、CCL2、IRF5 呈正相关(P 均<0.05),SMAD9 与CCL2、IRF5 呈正相关(P 均<0.05).相对于癌旁组织中 SMAD7(1.00±0.27)、SMAD9(1.00±0.31)的表达,癌组织中SMAD7(0.76±0.24)、SMAD9(0.81±0.22)的表达降低(P 均<0.05).SMAD7、SMAD9 低表达患者的 5 年总生存率低于高表达患者(P 均<0.05).Cox分析结果显示,淋巴结转移、T3+T4 分期、组织学Ⅲ级与SMAD7、SMAD9 水平是影响患者总生存时间的独立风险因素(P 均<0.05).结论 SMAD7、SMAD9 是预测肺腺癌不良预后的潜在生物分子,与免疫浸润水平相关,可能参与免疫细胞调节.