Objective: Small cell lung cancer (SCLC) is a high-grade neuroendocrine tumor characterized by initial sensitivity to chemotherapy, followed by the development of drug resistance. The underlying mechanisms of resistance in SCLC have not been fully elucidated. Aldo-keto reductase family 1 member C3 (AKR1C3), is known to be associated with chemoradiotherapy resistance in diverse tumors. We aim to evaluate the prognostic significance and immune characteristics of AKR1C3 and investigate its potential role in promoting drug resistance in SCLC. Methods: 81 postoperative SCLC tissues were used to analyze AKR1C3 prognostic value and immune features. The tissue microarrays were employed to validate the clinical significance of AKR1C3 in SCLC. The effects of AKR1C3 on SCLC cell proliferation, migration, apoptosis and tumor angiogenesis were detected by CCK-8, wound healing assay, transwell assay, flow cytometry and tube formation assay. Results: AKR1C3 demonstrated the highest expression level compared to other AKR1C family genes, and multivariate cox regression analysis identified it as an independent prognostic factor for SCLC. High AKR1C3 expression patients who underwent chemoradiotherapy experienced significantly shorter overall survival (OS). Furthermore, AKR1C3 was involved in the regulation of the tumor immune microenvironment in SCLC. Silencing of AKR1C3 led to the inhibition of cell proliferation and migration, while simultaneously promoting apoptosis and reducing epithelial-mesenchymal transition (EMT) in SCLC. Conclusion: AKR1C3 promotes cell growth and metastasis, leading to drug resistance through inducing EMT and angiogenesis in SCLC.

Multiple myeloma (MM) is an incurable hematological malignancy, and the number of MM patients is increasing year by year. Zinc finger protein 655 (ZNF655) has been shown to regulate various biological processes and is implicated in the progression of many diseases. However, the roles of ZNF655 in MM progression remains unclear. In this study, we aimed to explore the effects of ZNF655 on progression by detecting the alteration of the phenotypes and tumorigenesis induced by ZNF655 knockdown in MM. The expression level of ZNF655 in MM was clarified by real-time quantitative polymerase chain reaction assays. Furthermore, loss-of-function assays in vitro and in vivo was investigated the biological functions of ZNF655 in MM. These findings revealed that ZNF655 depletion remarkably inhibited MM cell proliferation, arrested cell cycle, and induced cell apoptosis. Mechanistically, ZNF655 was found to regulate AKT in MM. In conclusion, this study indicated that ZNF655 regulated the progression of MM via AKT activation and downregulation of ZNF655 may be a promising antitumor strategy in MM.

Background: Hypoxic ischemic brain damage(HIBD) cause permanent damage to the central nervous system (CNS), including mental retardation, aphasia, epilepsy, cerebral palsy, and developmental delays. Recently, human umbilical cord mesenchymal stem cells (hUC-MSCs) have emerged as a promising cell therapy in HIBD. The optimal dose of stem cell therapy remains open. Methods: Previously, we conducted a study to identify that the best route of administration of hUC-MSCs to HIBD rat model is intranasal transplantation. In this study, we conducted the comparison experiments for the optimal dose of MSC via the best route of administration, intranasal transplantation. Four different doses (0.5*106, 1.0*106, 1.5*106, 2.0*106) of hUC-MSCs were injected to HIBD rats (obtained HIBD at 7th day after birth) on the10th day after birth. The body weight, hanging wire test and Morris Water Maze test were used on the 28th day of different groups of rats to compare their motor function, memory, and learning ability. The HE staining was used to compare the morphological differences of brain tissues of rats in different groups. Moreover, the immunohistochemistry was adopted to compare the morphology and number of astrocytes and microglia in cortex and CA1, CA3 region of the brain of different groups. Results: All the four different doses of hUC-MSCs treatment significantly improved their body weight, the motor function, memory, learning ability, the morphology and number of astrocytes and microglia in cortex and CA1, CA3 region of HIBD rats. The 1.5*106 of hUC-MSCs group significantly outperform other three groups (0.5*106, 1.0*106, 2.0*106) on both neurobehavioral motor function improvement and morphological improvement, i.e., reducing the number of astrocytes and microglia in cortex and CA1, CA3 region of HIBD rats. The study suggests that 1.5*106 of hUC-MSCs was the optimal dose for rats who obtained HIBD at 7th day after birth and injected by intranasal transplantation on the 10th day after birth.

Although the initial research focused on glycolysis, mitochondrial oxidative phosphorylation has become a major target of cancer cells. Cytochrome C oxidase assembly factor 6 (COA6) is a conserved assembly factor necessary for complex IV biogenesis. Nevertheless, the clinical predictive value of COA6, especially its correlation with immune cell infiltration in lung adenocarcinoma (LUAD), has not yet been elucidated. COA6 exhibited higher expression levels in LUAD cells and tumor tissues compared to normal tissues. Additionally, heightened COA6 expression was associated with reduced overall survival (OS) and advanced tumor stage. Apart from its role in mitochondrial respiratory processes, COA6 may be involved in the process of antigen binding, immunoglobulin receptor binding. Interestingly, we observed a positive correlation between COA6 expression and tumor mutational burden (TMB), as well as a significant association with decreased immune cell infiltration. COA6 was linked to resistance against gemcitabine and etoposide. We verified that COA6 was highly expressed in LUAD experimentally and cell proliferation was inhibited after COA6 knockdown. Thus, we conclude that the expression of COA6 was correlated with reduced immune cell infiltration. Additionally, COA6 functioned as a biomarker for drug sensitivity and the prognosis of lung adenocarcinoma.

AbstractBackgroundEmerging evidence suggests a complex interplay between periodontal disease (PD) and coronary artery disease (CAD) risk. The novel insights into the shared pathogenesis of PD and CAD will potentially inform future therapeutic strategies. This study aimed to identify signature genes implicated in the progression of PD to CAD.MethodsGene expression data from NCBI GEO datasets, GSE10334 and GSE66360, associated with both PD and CAD datasets were analyzed to pinpoint differentially expressed genes (DEGs), followed by weighted gene co-expression network analysis (WGCNA) to identify key modules. Functional enrichment analysis of common DEGs was conducted. Four machine learning algorithms were employed to construct predictive models, and the optimal model was selected for subsequent feature genes selection. Using GSE6751 and GSE71226 as validation cohort, receiver operating characteristic (ROC) curves and nomograms were generated for diagnostic performance assessment and risk prediction. Furthermore, immune cell infiltration patterns were assessed using the CIBERSORT (Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts) algorithm. Finally, RNA-sequencing (RNA-seq) of 5 clinical samples vs. 5 controls was performed to validate the identified genes and explore their potential as biomarkers for early diagnosis and prevention of comorbid periodontitis and CAD.ResultsAnalysis of the GSE10334 and GSE66360 datasets revealed 48 common Differentially Expressed Genes (DEGs) associated with CAD and PD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of these DEGs highlighted significant overrepresentation of pathways related to inflammatory responses and immune cell trafficking, including response to lipopolysaccharides, molecules of bacterial origin, neutrophil migration, bone marrow leukocyte migration, and CXCR chemokine receptor binding. Additionally, pathways involved in lipid metabolism and atherosclerosis, such as the NF-κB signaling pathway, IL-17 signaling pathway, and TNF signaling pathway, were also enriched. Five genes (FOS, MME, PECAM1, RGS1,andVNN2) emerged as potential signature genes, demonstrating strong predictive ability with an area under the curve (AUC) greater than 0.7 on the machine learning algorithms. CIBERSORT analysis suggested a potential role of these signature genes in modulating immune cell infiltration. To further validate these findings, RNA-seq on clinical samples confirmed significant upregulation ofFOS,VNN2,PECAM1, andMMEgenes in patients with both CAD and PD.ConclusionThis study identified five signature genes that were significantly associated with immune cell dysregulation, where four of them were verified on clinical samples. These genes hold promise for the development of a nomogram-based approach for early diagnosis of both periodontitis and coronary artery disease, potentially informing future research directions for improved diagnosis and treatment strategies in these prevalent conditions. Notably, the prominent upregulation ofFOSsuggests its potential as a key target for future investigations. These insights hold significant implications for improving prevention and diagnostic strategies for individuals affected by both PD and CAD.

Background Mitochondria, which serve as the fundamental organelle for cellular energy and metabolism, are closely linked to the growth and survival of cancer cells. This study aims to identify and assess Sideroflexin1 (SFXN1), an unprecedented mitochondrial gene, as a potential prognostic biomarker for lung adenocarcinoma (LUAD). Methods The mRNA and protein levels of SFXN1 were investigated based on the Cancer Genome Atlas (TCGA) LUAD dataset, and then validated by real-time quantitative PCR, Western Blotting and immunohistochemistry from our clinical samples. The clinical correlation and prognostic value were evaluated by the TCGA cohort and verified via our clinical dataset ( n = 90). The somatic mutation, drug sensitivity data, immune cell infiltration and single-cell RNA sequencing data of SFXN1 were analyzed through public databases. Results SFXN1 was markedly upregulated at both mRNA and protein levels in LUAD, and high expression of SFXN1 were correlated with larger tumor size, positive lymph node metastasis, and advanced clinical stage. Furthermore, SFXN1 upregulation was significantly associated with poor clinical prognosis. SFXN1 co-expressed genes were also analyzed, which were mainly involved in the cell cycle, central carbon metabolism, DNA repair, and the HIF-1α signaling pathway. Additionally, SFXN1 expression correlated with the expression of multiple immunomodulators, which act to regulate the tumor immune microenvironment. Results also demonstrated an association between SFXN1 expression and increased immune cell infiltration, such as activated CD8 + T cells, natural killer cells (NKs), activated dendritic cells (DCs), and macrophages. LUAD patients with high SFXN1 expression exhibited heightened sensitivity to multiple chemotherapies and targeted drugs and predicted a poor response to immunotherapy. SFXN1 represented an independent prognostic marker for LUAD patients with an improved prognostic value for overall survival when combined with clinical stage information. Conclusions SFXN1 is frequently upregulated in LUAD and has a significant impact on the tumor immune environment. Our study uncovers the potential of SFXN1 as a prognostic biomarker and as a novel target for intervention in LUAD.

Abstract Resistance to paclitaxel poses a major obstacle in esophageal squamous cell carcinoma (ESCC) treatment. A better understanding of the mechanisms underlying paclitaxel resistance could help identify prognostic biomarkers and improved therapeutic strategies. In this study, we established a patient-derived xenograft model of acquired paclitaxel resistance and used RNA sequencing to identify galectin-1, encoded by LGALS1, as a key mediator of resistance. Integrative analysis of clinical data and physiological studies indicated that serum galectin-1 levels were elevated in resistant patients and correlated with treatment outcomes before and during taxane therapy. Importantly, exposing cells to serum from resistant patients resulted in increased paclitaxel resistance compared to serum from sensitive patients, which was closely associated with galectin-1 concentrations in the serum. The specific clearance of galectin-1 from resistant patient serum significantly restored paclitaxel sensitivity, and inhibiting galectin-1, through knockdown or the pharmacologic inhibitor OTX008, increased sensitivity to paclitaxel. Galectin-1 inhibition reduced the activity of β-catenin, thereby inhibiting stem cell properties induced by the Wnt/β-catenin pathway. Furthermore, galectin-1 regulated MDR1 transcription through increased nuclear accumulation of β-catenin, thus increasing resistance to paclitaxel. Combining OTX008 with clinical taxane formulations effectively reversed paclitaxel resistance in vitro and in vivo. Elevated galectin-1 levels thus serve as an indicator of response to paclitaxel therapy in ESCC, offering a therapeutic intervention strategy to overcome drug resistance. Significance: Galectin-1 is a key mediator of paclitaxel resistance in esophageal squamous cell carcinoma that can be targeted to improve taxane efficacy, suggesting broad therapeutic potential for treating various cancer types.

Background Immune checkpoint inhibitors (ICIs) can lead to life-threatening pneumonitis, and pre-existing interstitial lung abnormalities (ILAs) are a risk factor for checkpoint inhibitor pneumonitis (CIP). However, the subjective assessment of ILA and the lack of standardized methods restrict its clinical utility as a predictive factor. This study aims to identify non-small cell lung cancer (NSCLC) patients at high risk of CIP using quantitative imaging. Methods This cohort study involved 206 cases in the training set and 111 cases in the validation set. It included locally advanced or metastatic NSCLC patients who underwent ICI therapy. A deep learning algorithm labeled the interstitial lesions and computed their volume. Two predictive models were developed to predict the probability of grade ≥ 2 CIP or severe CIP (grade ≥ 3). Cox proportional hazard models were employed to analyze predictors of progression-free survival (PFS). Results In a training cohort of 206 patients, 21.4% experienced CIP. Two models were developed to predict the probability of CIP based on different predictors. Model 1 utilized age, histology, and preexisting ground glass opacity (GGO) percentage of the whole lung to predict grade ≥ 2 CIP, while Model 2 used histology and GGO percentage in the right lower lung to predict grade ≥ 3 CIP. These models were validated, and their accuracy was assessed. In another exploratory analysis, the presence of GGOs involving more than one lobe on pretreatment CT scans was identified as a risk factor for progression-free survival. Conclusions The assessment of GGO volume and distribution on pre-treatment CT scans could assist in monitoring and manage the risk of CIP in NSCLC patients receiving ICI therapy. Clinical relevance statement This study’s quantitative imaging and computational analysis can help identify NSCLC patients at high risk of CIP, allowing for better risk management and potentially improved outcomes in those receivingICI treatment.

BackgroundCyclin-dependent kinases (CDKs) play a key role in cell proliferation in lung adenocarcinoma (LUAD). Comprehensive analysis of CDKs to elucidate their clinical significance and interactions with the tumor immune microenvironment is needed.MethodsRNA expression, somatic mutation, copy number variation, and single-cell RNA sequencing data were downloaded from public datasets. First, we comprehensively evaluated the expression profile and prognostic characteristics of 26 CDKs in LUAD, and CDK1 was selected as a candidate for further analysis. Then, a systematic analysis was performed to explore the relationships of CDK1 with clinical characteristics and tumor immune microenvironment factors in LUAD.ResultsCDK1 was markedly upregulated at both the mRNA and protein level in LUAD. Moreover, overexpression of CDK1 was related to poor clinical outcomes. CDK1 coexpressed genes were mainly involved in the cell cycle, the DNA repair process, and the p53 signaling pathway. In addition, CDK1 expression was found to be correlated with the expression of multiple immunomodulators and chemokines, which participate in activating and suppressing the immune microenvironment. CDK1 expression was also correlated with increased infiltration of numerous immune cells, including CD4+ T cells and M1 macrophages. Patients with high CDK1 expression tended to have a poor response to immunotherapy but were sensitive to multiple chemotherapies and targeted drugs. The MDK-NCL and SPP1-CD44 ligand−receptor pairs were markedly activated in the intercellular communication network. CDK1 was an independent prognostic factor for LUAD and improved the ability to predict overall survival when combined with tumor stage.ConclusionCDK1 plays an essential role in reshaping the tumor immune microenvironment and might be a prognostic and treatment biomarker in LUAD.

Esophageal squamous precancerous lesions (ESPL) are the precursors of esophageal squamous cell carcinoma (ESCC) including low-grade and high-grade intraepithelial neoplasia. Due to the absence of molecular indicators, which ESPL will eventually develop into ESCC and thus should be treated is not well defined. Indicators, for predicting risks of ESCC at ESPL stages, are an urgent need. We perform spatial whole-transcriptome atlas analysis, which can eliminate other tissue interference by sequencing the specific ESPL regions. In this study, the expression of TAGLN2 significantly increases, while CRNN expression level decreases along the progression of ESCC. Additionally, TAGLN2 protein level significantly increases in paired after-progression tissues compared with before-progression samples, while CRNN expression decreases. Functional studies suggest that TAGLN2 promotes ESCC progression, while CRNN inhibits it by regulating cell proliferation. Taken together, TAGLN2 and CRNN are suggested as candidate indicators for the risk of ESCC at ESPL stages.

Lymphoma is the most common malignant tumor arising from immune system. Recently, DNA polymerase epsilon subunit 2 (POLE2) was identified to be a tumor promotor in a variety of malignant tumors. However, the biological role of POLE2 in lymphoma is still largely unclear. In our present study, the expression patterns of POLE2 in lymphoma tissues were identified by immunohistochemistry (IHC) staining of human tissue microarray. Cell viability was determined by CCK-8 assay. Cell apoptosis and cycle distribution were evaluated by Annexin V and PI staining, respectively. Cell migration was analyzed by transwell assay. Tumor growth in vivo was observed by a xenograft model of mice. The potential signaling was explored by human phospho-kinase array and immunoblotting. POLE2 was significantly upregulated in human lymphoma tissues and cells. POLE2 knockdown attenuated the proliferation, migration capabilities of lymphoma cells, as well as induced cell apoptosis and cycle arrest. Moreover, POLE2 depletion impaired the tumor growth in mice. Furthermore, POLE2 knockdown apparently inhibited the activation of β-Catenin and downregulated the expression of Wnt/β-Catenin signaling-related proteins. POLE2 knockdown suppressed the proliferation and migration of lymphoma cells by inhibiting Wnt/β-Catenin signaling pathway. POLE2 may serve as a novel therapeutic target for lymphoma.

The molecular and pathogenic mechanisms of esophageal squamous cell carcinoma (ESCC) development are still unclear, which hinders the development of effective treatments. In this study, we report that DUSP4 is highly expressed in human ESCC and is negatively correlated with patient prognosis. Knockdown of DUSP4 suppresses cell proliferation and patient-derived xenograft (PDX)-derived organoid (PDXO) growth and inhibits cell-derived xenograft (CDX) development. Mechanistically, DUSP4 directly binds to heat shock protein isoform β (HSP90β) and promotes the ATPase activity of HSP90β by dephosphorylating HSP90β on T214 and Y216. These dephosphorylation sites are critical for the stability of JAK1/2-STAT3 signaling and p-STAT3 (Y705) nucleus translocation. In vivo, Dusp4 knockout in mice significantly inhibits 4-nitrochinoline-oxide-induced esophageal tumorigenesis. Moreover, DUSP4 lentivirus or treatment with HSP90β inhibitor (NVP-BEP800) significantly impedes PDX tumor growth and inactivates the JAK1/2-STAT3 signaling pathway. These data provide insight into the role of the DUSP4-HSP90β-JAK1/2-STAT3 axis in ESCC progression and describe a strategy for ESCC treatment.

Epidemiological evidence supports that consumption of high‐temperature food and beverages is an important risk factor for esophageal squamous cell carcinoma (ESCC); however, the underlying mechanism still remains unclear. Here, we established a series of animal models and found that drinking 65°C water can promote esophageal tumor progression from preneoplastic lesions to ESCC. RNA sequencing data showed that miR‐132‐3p was highly expressed in the heat stimulation group compared with controls. Further study verified that miR‐132‐3p were upregulated in human premalignant lesion tissues of the esophagus, ESCC tissues, and cells. Overexpression of miR‐132‐3p could promote ESCC cell proliferation and colony formation, whereas knockdown of miR‐132‐3p could inhibit ESCC progression in vitro and in vivo. Importantly, dual‐luciferase reporter assays showed that miR‐132‐3p could bind with the 3′‐untranslated region of KCNK2 and inhibit KCNK2 gene expression. Knockdown or overexpression of KCNK2 could promote or suppress ESCC progression in vitro. These data suggest that heat stimulation can promote ESCC progression and miR‐132‐3p mediated this process by directly targeting KCNK2.

BackgroundAlthough targeted therapies and immunotherapy have achieved significant clinical benefits in patients with certain pathological types of lung cancer. However, prognosis for patients with lung adenocarcinoma still remains unsatisfactory. It is of extremely importance to find ideal prognostic indicators to predict the prognosis of lung adenocarcinoma patients, especially for patients with early and locally advanced-stage lung adenocarcinoma. The purpose of this study is to elucidate the significance of Insulin-like growth factor receptor 1 (IGFR1) and Vascular endothelial growth factor A (VEGF-A) expression in predicting progression-free survival (PFS) and overall survival (OS) in patients with early and locally advanced-stage lung adenocarcinoma.MethodsIn this study, IGFR1 and VEGF-A expression on 119 specimens of patients early and locally advanced-stage lung adenocarcinoma were analyzed by immunohistochemistry with an H-score system.ResultsBoth high IGFR1 expression and VEGF-A expression patients were resulted in 59 (49.6%) separately. The numbers and proportions of IGFR1-&VEGF-A- subgroup, IGFR1-&VEGF-A+ subgroup, IGFR1+&VEGF-A- subgroup and IGFR1+&VEGF-A+ subgroup are 23 (19.3%), 37 (31.1%), 37 (31.1%) and 22 (18.5%) respectively. High IGFR1 expression was significantly associated with both poor PFS and OS of all patients in a univariate analysis. Multivariable analysis showed that patients with IGFR1+&VEGF-A+ expression exhibited a worst PFS and OS in the subgroup of lung adenocarcinoma patients with EGFR mutation.ConclusionsThese results suggest that IGFR1+&VEGF-A+ is expected to be a disadvantageous factor for prognosis in the subgroup of EGFR mutation in patients with early and locally advanced-stage lung adenocarcinoma. What's more, this study may provide the theoretical possibility to screen optimal population for a combination therapy with anti-VEGF and anti-IGFR1 in patients with early and locally advanced-stage lung adenocarcinoma.

A comprehensive search regarding programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor monotherapy or combination therapy in neoadjuvant settings of 11 types of solid cancer was performed using the PubMed, Cochrane and Embase databases, and the abstracts of various conferences were screened. Data presented in 99 clinical trials indicated that preoperative treatment with PD-1/PD-L1 combined therapy, particularly immunotherapy plus chemotherapy, could achieve a higher objective response rate, a higher major pathologic response rate and a higher pathologic complete response rate, as well as a lower number of immune-related adverse events compared with PD-1/PD-L1 monotherapy or dual immunotherapy. Although PD-1/PD-L1 inhibitor combination caused more treatment-related adverse events (TRAEs) in patients, most of the TRAEs were acceptable and did not cause marked delays in operation. The data suggest that patients with pathological remission after neoadjuvant immunotherapy exhibit improved postoperative disease-free survival compared with those without pathological remission. Further studies are still required to evaluate the long-term survival benefit of neoadjuvant immunotherapy.

Esophageal squamous cell carcinoma (ESCC), is the most common type of esophageal cancer worldwide, mainly occurring in the Asian esophageal cancer belt, including northern China, Iran, and parts of Africa. Phosphatidlinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway is one of the most important cellular signaling pathways, which plays a crucial role in the regulation of cell growth, differentiation, migration, metabolism and proliferation. In addition, mutations in some molecules of PI3K/Akt/mTOR pathway are closely associated with survival and prognosis in ESCC patients. A large number of studies have found that there are many molecules in ESCC that can regulate the PI3K/Akt/mTOR pathway. Overexpression of these molecules often causes aberrant activation of PI3K/Akt/mTOR pathway. Currently, several effective PI3K/Akt/mTOR pathway inhibitors have been developed, which can play anticancer roles either alone or in combination with other inhibitors. This review mainly introduces the general situation of ESCC, the composition and function of PI3K/Akt/mTOR pathway, and regulatory factors that interact with PI3K/Akt/mTOR signaling pathway. Meanwhile, mutations and inhibitors of PI3K/Akt/mTOR pathway in ESCC are also elucidated.

Background Mitochondria are the core organelle of cellular energy and metabolism, also closely related to the growth and survival of cancer cells. This research aimed to discover and evaluate a promising prognostic biomarker, a novel mitochondrial gene—Sideroflexin1 (SFXN1), for lung adenocarcinoma (LUAD). Results Analysis of 594 samples from The Cancer Genome Atlas (TCGA) Lung Cancer Cohort, this present study indicated that SFXN1/2/4/5 were overexpressed in LUAD tissue compared with normal lung tissue whereas only the SFXN1 was associated significantly with the overall survival (OS) from the Kaplan-Meier survival analysis (p=0.00093), suggesting that SFXN1 could be a potential prognostic biomarker. Furthermore, the logistic regression of the correlation of clinicopathological features and the expression status of SFXN1 from 522 patients with LUAD in TCGA revealed that the expression level of SFXN1 was related to Eastern Cooperative Oncology Group (ECOG), clinical stage, tumor size and lymph nodes invasion (all p<0.05). Additionally, overexpression of SFXN1 remained associated positively and independently with a worse prognosis after the multivariate Cox regression (HR=1.486, p=0.022). Functionally, SFXN1 involved in the cell cycle, specifically in DNA replication and meiosis, ATPase activity and folate-dependent one-carbon metabolism from the outcomes of Eastern Cooperative Oncology Group (KEGG) and Gene Ontology (GO) enrichment. Conclusion SFXN1 might promote the proliferation and metabolism of cancer cells and function as a prognostic indicator for LUAD, which may contribute to the development of targeted therapy and the emergence of metabolism-based treatment in clinical practice.

Background The clinical benefit of immunotherapy has been limited to a small subset of patients with cancer. Several clinical trials with immune checkpoint inhibitors in multiple cancers have shown some improvement in obese patients. However, how obesity regulates the immune microenvironment remains unclear. Methods Bioinformatic analysis was used to discover immune microenvironmental‐related genes associated with body mass index (BMI). The expression of ICOS in tumor tissues was detected using western blot, immunohistochemistry, quantitative real‐time polymerase chain reaction (RT‐qPCR) and flow cytometry. RT‐qPCR was used to measure the expression of miR‐27a‐3p. The interaction between miR‐27a‐3p and ICOS was confirmed by dual‐luciferase reporter assay. Functional testing of T cells based on proliferation and interferon (IFN)‐gamma secretion was performed using ELISA and flow cytometry. Results ICOS, an immune microenvironment‐related gene, was significantly upregulated in obese patients with lung adenocarcinoma (LUAD). MiR‐27a‐3p showed a negative correlation with ICOS and suppressed the expression of ICOS. We determined that dipocyte‐derived exo‐miR‐27a‐3p could alter the tumor microenvironment by inhibiting ICOS+ T cell proliferation and IFN‐gamma secretion in vitro. Conclusions Adipocyte‐derived exo‐miR‐27a‐3p can inhibit ICOS+ T cell proliferation and IFN‐gamma secretion. The upregulation of ICOS+ T cell functions caused by the downregulation of miR‐27a‐3p in adipose tissue derived exosomes is one of the potential mechanisms for the improved efficacy of immunotherapy in obese LUAD patients.