Journal of gastrointestinal oncology最新文献

{"title":"Colorectal cancer prognosis: insights from the tumor immune microenvironment and gut microbiota.","authors":"Quan Chen, Youtao Zhou, Zikai Lin, Cuiyan Yang, Hui Chen, Chuanfeng Ke","doi":"10.21037/jgo-2025-517","DOIUrl":"10.21037/jgo-2025-517","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is the third most common cancer worldwide. Despite recent advancements in screening strategies and treatments, the prognosis of CRC patients remains poor. Emerging evidences suggest that tumor immune microenvironment (TIME) and gut microbiota play a pivotal role in CRC progression and treatment. However, the clinical utility of these findings remains limited due to the absence of robust biomarkers. We sought to establish a clinically actionable tool that could guide personalized treatment decisions and ultimately improve outcomes for CRC patients.</p><p><strong>Methods: </strong>We analyzed differentially expressed genes (DEGs) from the Gene Expression Omnibus (GEO) and identified the prognostic genes for CRC by integrating the TIME- and gut microbiota-related genes from GeneCards. Using Mendelian randomization (MR), we examined the causal relationships between the prognostic genes, gut microbiota, and CRC. We then developed a risk model and independently validated its predictive performance using The Cancer Genome Atlas-Colon Adenocarcinoma (TCGA-COADREAD) dataset as an external validation cohort.</p><p><strong>Results: </strong>We established a risk model comprising the six identified genes and found that the high-risk group had a significantly higher mortality rate than the low-risk group. Additionally, the high-risk group showed increased immune cell infiltration and a diminished response to immunotherapy. The two-step MR analysis revealed that <i>Deltaproteobacteria</i> and <i>Methanobrevibacter</i> mediated the causal relationship between the prognostic genes and CRC. Further, the risk score was shown to be an independent prognostic factor for CRC survival, and the newly established nomogram demonstrated strong concordance between the predicted and observed clinical outcomes.</p><p><strong>Conclusions: </strong>We developed a six-gene risk model and showed that gut microbes mediate the causal link between the prognostic genes and CRC. Further research on the regulation of the TIME and gut microbiota in CRC may provide valuable insights.</p>","PeriodicalId":15841,"journal":{"name":"Journal of gastrointestinal oncology","volume":"16 4","pages":"1521-1533"},"PeriodicalIF":2.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of stereotactic body radiotherapy in hepatocellular carcinoma with adrenal metastases: a retrospective analysis.","authors":"Xi Cheng, Jing Li, Yong Li, Fenghua Liu, Tiehua Li, Yan Meng, Miaomiao Wang","doi":"10.21037/jgo-2024-1011","DOIUrl":"10.21037/jgo-2024-1011","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) with adrenal metastasis is associated with poor prognosis and lacks standardized treatment strategies. Stereotactic body radiotherapy (SBRT) is a promising non-invasive option, yet its efficacy in this setting remains underexplored. This study aims to evaluate the efficacy and safety of SBRT in managing HCC patients with adrenal metastasis, focusing on factors influencing local control (LC) and overall survival (OS).</p><p><strong>Methods: </strong>This retrospective study included 52 HCC patients with adrenal metastases treated with SBRT using the CyberKnife system between February 2016 and March 2022. Gross tumor volume (GTV) and biologically effective dose (BED) were calculated, and LC and OS were analyzed. Prognostic factors were assessed using univariate and multivariate Cox regression.</p><p><strong>Results: </strong>At a median follow-up of 12.5 months, the overall response rate was 86.0%, with LC rates of 100%, 81.7%, and 75.8% at 6 months, 1 year, and 2 years, respectively. The median OS was 22 months. Intrahepatic tumor control and absence of extra-organ metastases were independently associated with improved OS (P=0.01 and P=0.001, respectively). No grade ≥2 adverse reactions were observed.</p><p><strong>Conclusions: </strong>CyberKnife-based SBRT provides high LC rates and acceptable survival outcomes in HCC patients with adrenal metastases. Intrahepatic lesion control and extrahepatic disease burden are key factors influencing prognosis. SBRT should be considered as a local treatment strategy in multidisciplinary management of this population.</p>","PeriodicalId":15841,"journal":{"name":"Journal of gastrointestinal oncology","volume":"16 4","pages":"1610-1621"},"PeriodicalIF":2.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fear of cancer recurrence and associated factors in Chinese patients with colorectal cancer: a cross-sectional study.","authors":"Lijuan Xu, Wenli Dai, Li Chen, Lifeng Yao","doi":"10.21037/jgo-2025-503","DOIUrl":"10.21037/jgo-2025-503","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Colorectal cancer (CRC) is rising globally, with China bearing the highest burden. Fear of cancer recurrence (FCR) significantly impacts postoperative patients' well-being but remains understudied in China. The roles of illness perception, emotional distress, and social support in FCR are unclear. This study aims to assess FCR levels and identify influencing factors to guide early clinical intervention.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;From November 2023 to May 2024, a cross-sectional survey was conducted among 314 postoperative CRC patients at a tertiary cancer hospital in Shanghai. Eligible adults (≥18 years) with confirmed CRC who had completed primary treatment were recruited via convenience sampling. Validated questionnaires were completed independently or with staff assistance. These included the Fear of Cancer Recurrence Inventory (FCRI), the Brief Illness Perception Questionnaire (BIPQ), the Social Support Rating Scale (SSRS), the 15-Item Social Constraints Scale (SCS-15), and the Hospital Anxiety and Depression Scale (HADS). Pearson correlation analysis was conducted to examine associations among FCR, illness perception, social factors, and psychological symptoms. Subsequently, multivariable logistic regression was conducted to identify independent predictors of high FCR.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Of the 330 questionnaires distributed, 314 were deemed valid, yielding a response rate of 95.2%. The sample included 193 males (61.5%) and 121 females (38.5%), with a mean age of 59.7±12.3 years. Participants showed a high level of FCR, with a mean FCRI score of 69.64±27.10 and severity dimension score of 13.91±5.996. Univariate analysis revealed significant differences in age, monthly income, and residence between high and low-to-moderate FCR groups (P&lt;0.05). The high FCR group had greater illness perception (BIPQ), higher social constraints (SCS-15), elevated anxiety and depression (P&lt;0.001), and lower social support (SSRS; P=0.01) compared to the low-to-moderate group. Correlation analysis showed that FCR was significantly positively correlated with illness perception (r=0.548, P&lt;0.01), social constraints (SCS-15; r=0.275, P&lt;0.01), and psychological distress, including anxiety (r=0.596, P&lt;0.01) and depression (r=0.426, P&lt;0.01), highlighting the interplay among cognitive, social, and emotional factors. Subsequent binary logistic regression analysis identified illness perception and anxiety symptoms as significant independent predictors of FCR in patients with CRC.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;FCR is common among postoperative CRC patients and is strongly linked to illness perception and anxiety. These findings underscore the need for routine psychological screening and tailored communication. Interventions addressing maladaptive beliefs and emotional distress, along with integrated psychoeducational and psychosocial support, may enhance resilience and improve quality of life in survivorship care.&lt;/p","PeriodicalId":15841,"journal":{"name":"Journal of gastrointestinal oncology","volume":"16 4","pages":"1534-1549"},"PeriodicalIF":2.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of prognostic biomarkers in colorectal cancer through multi-omics profiling of programmed cell death pathways.","authors":"Song Qiao, Shangzhen Yang, Hua Hua, Chengtao Mao, Xiaolong Li, Cai Cheng, Hongguo Guo, Wanling Lu","doi":"10.21037/jgo-2024-861","DOIUrl":"10.21037/jgo-2024-861","url":null,"abstract":"<p><strong>Background: </strong>Programmed cell death (PCD) pathways, including autophagy, ferroptosis, cuproptosis, neutrophil extracellular trap formation (NETosis), and paraptosis, are central to tumor biology and hold potential as therapeutic targets in colorectal cancer (CRC). The aim of this study is to use multi-omics data to analyze the role of PCD in CRC.</p><p><strong>Methods: </strong>We conducted a multi-omics analysis using data from The Cancer Genome Atlas (TCGA), single-cell sequencing, and spatial transcriptomics to investigate the expression profiles, prognostic significance, and functional effects of PCD-associated genes in CRC. Key prognostic genes were identified through gene set variation analysis (GSVA), single-sample gene set enrichment analysis (ssGSEA), univariate Cox regression, and least absolute shrinkage and selection operator (LASSO) regression modeling.</p><p><strong>Results: </strong>Our analysis identified five PCD pathways with significant prognostic relevance in CRC, particularly autophagy and cuproptosis. Pan-cancer analyses highlighted unique and shared expression patterns of PCD-related genes across diverse cancer types, revealing their differential roles in cancer progression. Dynamic network biomarker (DNB) modeling pinpointed stage-specific critical transitions in PCD pathway activity, suggesting temporal variations in pathway influence on tumor progression. Functional assays demonstrated that overexpression of nuclear receptor coactivator 4 (<i>NCOA4</i>), an autophagy-related gene, suppressed CRC cell migration and invasion while promoting apoptosis, validating its anti-tumor role in CRC.</p><p><strong>Conclusions: </strong>This study underscores the prognostic significance of PCD pathways in CRC, highlighting their potential as biomarkers and therapeutic targets. By identifying core genes within these pathways and elucidating their temporal effects on tumor progression, we provide a comprehensive foundation for future research into PCD-targeted therapies in CRC, aiming to enhance personalized treatment strategies.</p>","PeriodicalId":15841,"journal":{"name":"Journal of gastrointestinal oncology","volume":"16 4","pages":"1503-1520"},"PeriodicalIF":2.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world second-line treatment pattern for unresectable or advanced hepatic carcinoma in China: a retrospective database study.","authors":"Jiahua Leng, Jing Wu, Rong Han, Huan Wei, Ken Chen","doi":"10.21037/jgo-2024-1015","DOIUrl":"10.21037/jgo-2024-1015","url":null,"abstract":"<p><strong>Background: </strong>In recent years, the emerging new drugs in the Chinese market diversified the choice of systemic treatment, especially second-line (2L), for unresectable or advanced hepatic carcinoma (HC) patients, and their inclusion into the National Reimbursement Drug List (NRDL) further changed the clinical practice. The objective of this study was to describe the 2L treatment pattern among Chinese unresectable or advanced HC patients in a real-world setting.</p><p><strong>Methods: </strong>All adult unresectable or advanced HC patients receiving 2L treatment were retrospectively identified from Tianjin Healthcare and Medical Big Data Platform, a regional electronic health record database in Tianjin, China. Patients were observed between 2018 and 2021. A descriptive analysis was conducted for study outcomes for the overall cohort and by subgroups before and after NRDL 2020 version implementation.</p><p><strong>Results: </strong>A total of 123 patients were eligible for study inclusion. Targeted therapy (n=93, 75.6%) was the most commonly used 2L treatment category and regorafenib monotherapy (n=71, 57.7%) was the most common treatment type. Among patients receiving regorafenib as 2L treatment, sorafenib was the most commonly used first-line treatment. The percentage of patients using 2L treatments recommended by 2020 China Society of Clinical Oncology (CSCO) guideline changed from 87.2% to 59.2% after NRDL 2020 version implementation. The average daily doses of targeted therapies were generally lower than the labeling doses, while those of immune therapies were close to labeling doses. There was a trend towards increased treatment duration and reduced direct medical cost after NRDL 2020 version implementation.</p><p><strong>Conclusions: </strong>Targeted therapy, especially regorafenib, was the most common 2L treatment for unresectable or advanced HC in China. Future study is necessary to evaluate their effectiveness and safety as 2L treatment for unresectable or advanced HC patients in China.</p>","PeriodicalId":15841,"journal":{"name":"Journal of gastrointestinal oncology","volume":"16 4","pages":"1597-1609"},"PeriodicalIF":2.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rethinking surrogate endpoints in metastatic colorectal cancer: counting chickens only when they hatch.","authors":"Luis I Ruffolo, Michael D'Angelica","doi":"10.21037/jgo-2025-386","DOIUrl":"10.21037/jgo-2025-386","url":null,"abstract":"","PeriodicalId":15841,"journal":{"name":"Journal of gastrointestinal oncology","volume":"16 4","pages":"1763-1767"},"PeriodicalIF":2.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DDX18 promotes growth and metastasis of hepatocellular carcinoma via activating EMT and MAPK signaling.","authors":"Xiaodong Xu, Xiaoxia Yu, Nannan Zhang, Feiran Wang, Zhong Chen","doi":"10.21037/jgo-2025-339","DOIUrl":"10.21037/jgo-2025-339","url":null,"abstract":"<p><strong>Background: </strong>DDX18, a member of the DEAD-box RNA helicase family, plays a pivotal role in ribosome biogenesis and RNA metabolism and is thus extensively implicated in tumorigenesis. Although its oncogenic functions have been well-documented across various malignancies, the precise molecular mechanisms underlying DDX18-driven progression in hepatocellular carcinoma (HCC) remain largely undefined. This study systematically elucidates the pathological contributions of DDX18 to HCC through a combination of comprehensive <i>in vitro</i> experiments and <i>in vivo</i> analyses.</p><p><strong>Methods: </strong>We assessed the expression and effects of DDX18 on HCC tissues and cellular functions through bioinformatics analyses, wound healing assays, colony formation assays, transwell assays, and flow cytometry. Western blot analysis revealed that mitogen-activated protein kinase (MAPK) signaling pathways were associated with protein levels involved in the epithelial-mesenchymal transition (EMT). Co-immunoprecipitation (Co-IP) and immunoFluorescence colocalization experiments confirmed the interaction between DDX18 and REXO4. Additionally, we evaluated the functional roles of DDX18 and REXO4 using a series of <i>in vitro</i> assays and nude mouse xenograft models.</p><p><strong>Results: </strong>Our data demonstrated elevated expression of DDX18 in HCC tissues. DDX18 significantly increased cell proliferation, invasion, and migration, and activated EMT and MAPK signaling pathways <i>in vitro</i>. Mechanistically, DDX18 interacts with REXO4, thereby promoting tumor growth and metastasis by regulating the EMT process and MAPK signaling. Furthermore, overexpression of REXO4 reversed the inhibitory effects of DDX18 knockdown both <i>in vitro</i> and <i>in vivo</i>.</p><p><strong>Conclusions: </strong>This study provides evidence that the DDX18/REXO4 axis plays a critical role in HCC development and may represent a novel therapeutic target or diagnostic biomarker for patients with HCC.</p>","PeriodicalId":15841,"journal":{"name":"Journal of gastrointestinal oncology","volume":"16 4","pages":"1622-1634"},"PeriodicalIF":2.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12433112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local radiotherapy polarized tumor-associated macrophages enhance the efficacy of Claudin18.2-targeted CAR-T therapy in pancreatic cancer.","authors":"Xiaokang Zhang, Hongtai Shi, Leran Qiu, Zhunyi Gao, Jiahe Xu, Xingyu Zhou, Zeya Xia, Ganesh Radhakrishna, Jiao Xue, Songbing Qin","doi":"10.21037/jgo-2025-564","DOIUrl":"10.21037/jgo-2025-564","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, and a 5-year survival rate of less than 10%. Its dense, immunosuppressive tumor microenvironment (TME) limits the effectiveness of conventional therapies, including immunotherapy. Chimeric antigen receptor T-cell (CAR-T) therapy targeting the tight junction protein claudin18.2 (CLDN18.2) has shown promise in preclinical PDAC studies, but its efficacy is severely constrained by immunosuppressive components in the TME, such as tumor-associated macrophages (TAMs). In addition to directly killing tumor cells, radiotherapy (RT) can modulate the TME, promote immune cell infiltration, and potentially enhance the efficacy of CAR-T in solid tumors. This study aimed to investigate the effects of combining RT with CLDN18.2-targeted CAR-T therapy for PDAC, focusing on elucidating whether RT can overcome the major barriers to immunotherapy in PDAC by reshaping the immunosuppressive TME and enhancing CAR-T infiltration and function.</p><p><strong>Methods: </strong>Second-generation anti-CLDN18.2 CAR-Ts with high transduction efficiency were generated. <i>In vitro</i>, we assessed the cytotoxicity of CAR-Ts against PDAC cells expressing CLDN18.2 both with and without prior irradiation. <i>In vivo</i>, the combination of RT and CAR-T therapy was tested in PDAC-bearing mice, and survival and tumor growth were monitored. The immune response and TME were analyzed for CAR-T infiltration, effector function production [tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and granzyme B], and immune cell composition (Tregs, MDSCs, and M1 macrophages).</p><p><strong>Results: </strong><i>In vitro</i>, the CAR-Ts exhibited potent cytotoxicity against the CLDN18.2-positive PDAC cells, and the efficacy was enhanced in the irradiated PDAC cells compared to the non-irradiated control PDAC cells. <i>In vivo</i>, local RT combined with CAR-T therapy significantly prolonged survival and delayed tumor growth in the PDAC-bearing mice. Additionally, the combination therapy increased the CAR-T infiltration and effector functions. Local RT also reshaped the TME by increasing M1 macrophages and reducing M2 macrophages.</p><p><strong>Conclusions: </strong>Local RT significantly enhanced the anti-tumor efficacy of CLDN18.2-targeted CAR-T therapy against PDAC. <i>In vitro</i>, RT increased CAR-T cytotoxicity against CLDN18.2-positive PDAC cells. <i>In vivo</i>, combining RT with CAR-T therapy prolonged survival and delayed tumor growth in tumor-bearing mice. This synergy resulted from RT promoting CAR-T infiltration and effector function, while reshaping the tumor microenvironment (TME) by increasing pro-inflammatory M1 macrophages and reducing immunosuppressive M2 macrophages. These findings show the potential of this combination approach as a promising therapeutic strategy for improving outcomes in PDAC patients.</p>","PeriodicalId":15841,"journal":{"name":"Journal of gastrointestinal oncology","volume":"16 4","pages":"1682-1698"},"PeriodicalIF":2.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12433137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NKAP overexpression promotes gastric cancer immune escape by inducing IL-10 secretion from mature dendritic cells during anti-PD-L1 therapy.","authors":"Bingna Yan, Pei Zhang, Qianhe Zu, Shan Liu, Pan Wang, Yaning Wei, Jialin Liu, Shun Zhang, Yanan Wang, Zhe Han","doi":"10.21037/jgo-2025-491","DOIUrl":"10.21037/jgo-2025-491","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC) remains a major clinical challenge due to its high mortality and propensity for immune escape, which critically limits the efficacy of immunotherapy. The immunosuppressive tumor microenvironment (TME) is a key factor restricting the effectiveness of immune checkpoint inhibitors (ICIs) in GC. The nuclear factor kappa B (NF-κB) activating protein (NKAP), a conserved regulator of the NF-κB pathway, has been shown to drive immune evasion in other cancer types by modulating cytokine networks and immune cell functions. However, the specific role and mechanisms of NKAP in shaping the immunosuppressive TME of GC and contributing to resistance against programmed death ligand 1 (PD-L1) blockade therapy remain largely unexplored. Therefore, this study aimed to investigate the role of NKAP in the GC TME and elucidate its mechanisms in driving immune escape and resistance to anti-PD-L1 therapy.</p><p><strong>Methods: </strong>We analyzed datasets from The Cancer Genome Atlas (TCGA) datasets and clinical specimens from patients with GC who received neoadjuvant therapy with PD-L1 inhibitors to evaluate NKAP expression and its association with clinicopathological features. <i>In vitro</i> models of mature dendritic cells (mDCs) and murine xenografts were used to investigate the mechanism underlying NKAP's involvement. NF-κB pathway activation, interleukin-10 (IL-10) secretion, and regulatory T cell (Treg) differentiation were assessed via luciferase assays, enzyme-linked immunosorbent assay, and flow cytometry. Changes in the TME and the therapeutic efficacy of PD-L1 blockade were evaluated in xenograft models.</p><p><strong>Results: </strong>Elevated NKAP expression correlated with advanced tumor-node-metastasis (TNM) stage, lymph node metastasis, and poor tumor differentiation in patients with GC. High NKAP levels predicted higher residual tumor burden post-PD-L1 therapy. Mechanistically, NKAP overexpression activated the NF-κB pathway in mDCs, driving IL-10 secretion and promoting naïve T-cell differentiation into immunosuppressive Tregs. This process fostered an immunosuppressive TME, which diminished the efficacy of PD-L1 blockade in murine models.</p><p><strong>Conclusions: </strong>NKAP is a critical regulator of GC immune escape, linking NF-κB-driven IL-10 production in mDCs to Treg-mediated immunosuppression during anti-PD-L1 therapy. Targeting NKAP may reverse resistance to ICIs, offering a promising strategy for improving clinical outcomes in patients with GC.</p>","PeriodicalId":15841,"journal":{"name":"Journal of gastrointestinal oncology","volume":"16 4","pages":"1443-1460"},"PeriodicalIF":2.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GBA3 as a regulator of sphingolipid metabolism in the progression of hepatocellular carcinoma.","authors":"Xuehong Wang, Lanyu Li, Tian Sun, Zhidong Qiu","doi":"10.21037/jgo-2025-567","DOIUrl":"10.21037/jgo-2025-567","url":null,"abstract":"<p><strong>Background: </strong>The prognosis and clinical treatment of hepatocellular carcinoma (HCC), one of the most prevalent malignant tumors, remains significantly challenging, underscoring the urgent need for novel biomarkers and therapeutic strategies to improve patient outcomes. Our study investigated the clinical significance and biological functions of glucosylceramidase beta 3 (GBA3) in HCC progression.</p><p><strong>Methods: </strong>GBA3 expression was analyzed in 39 paired HCC and adjacent non-tumor tissues, validated in The Cancer Genome Atlas (TCGA) dataset, and further confirmed via immunohistochemistry (IHC) in 90 additional paired specimens. The connection between GBA3 expression and clinical outcomes was analyzed through use of TCGA data and Kaplan-Meier survival analysis. The functional roles of GBA3 were examined through knockdown experiments in HCC cells, with proliferation, migration, and invasion being evaluated. Mechanistic studies were conducted to clarify the link between GBA3 downregulation and ceramide metabolism via ceramide synthase 3 (CerS3).</p><p><strong>Results: </strong>The expression of GBA3 messenger RNA (mRNA) and protein were significantly downregulated in HCC tissues as compared to non-tumor tissues. Low GBA3 expression correlated with advanced HCC and shorter patient survival. Functional assays demonstrated that GBA3 knockdown enhanced HCC cell proliferation, migration, and invasion. Mechanistically, GBA3 downregulation reduced CerS3 expression, disrupting ceramide metabolism and promoting HCC progression.</p><p><strong>Conclusions: </strong>GBA3 downregulation in HCC is related to the aggressive behavior and poor prognosis, indicating its potential as a sphingolipid metabolism-related prognostic biomarker and therapeutic target for HCC.</p>","PeriodicalId":15841,"journal":{"name":"Journal of gastrointestinal oncology","volume":"16 4","pages":"1635-1647"},"PeriodicalIF":2.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}