The impact of postoperative and oncologic outcomes between laparoscopic (L) and open (O) surgical approaches for the resection of gastric gastrointestinal stromal tumors (G-GISTs) located in surgically unfavorable regions remains controversial. A retrospective analysis was conducted on 699 patients who underwent primary resection of G-GISTs at surgically unfavorable locations across 14 centers in China between 2001 and 2017. The patients were categorized into L and O surgery groups. To reduce bias due to baseline differences, propensity score matching (PSM) and multivariate Cox proportional hazards models were employed. Postoperative recovery metrics and long-term oncologic outcomes were compared between the matched cohorts. After 1:1 PSM, the L group exhibited a significantly shorter and lower postoperative hospital stay, intraoperative estimated blood loss and postoperative complication rate compared to the O group (all P < .010). Kaplan–Meier survival analysis with log-rank testing revealed no statistically significant differences in overall survival (OS) between the two groups (P = .190). Multivariate Cox proportional hazards analysis further indicated that the L approach was not associated with a significant reduction in mortality risk (hazard ratio [HR]: 1.41; 95

BACKGROUND:Laparoscopic surgery has been increasingly adopted in the treatment of gastric cancer. Although the safety and efficacy of laparoscopic distal gastrectomy have been well established, evidence regarding laparoscopic total gastrectomy (LTG) remains limited, especially for early-stage disease. This study aimed to compare the short-term surgical outcomes and long-term survival between LTG and open total gastrectomy (OTG) in patients with stage 0-I gastric cancer. METHODS:A retrospective analysis was conducted on the clinicopathological data of 122 patients with stage 0-I gastric cancer underwent radical LTG or OTG from January 2010 to December 2013. Multivariate regression with a generalized estimation equation (GEE) was used to analyze the differences in total complications, LTG-related complications and OTG-related complications between the laparoscopic and open groups. The inverse probability of treatment weighting (IPTW) Kaplan-Meier survival curve was used to compare the long-term survival of the two groups. The primary outcome was the short-term outcomes and long-term survival of LTG with traditional OTG for stage 0-I gastric cancer. RESULTS:The incidence of postoperative complications was 16.4% in the LTG group and 18.4% in the OTG group, with no statistically significant difference between the two groups (P>0.05). In the adjusted multivariate GEE regression for OTG-related complications, the risk of OTG-related complications in the laparoscopic group was 0.111 (95% confidence interval: 0.016-0.771, P=0.03). Before and after IPTW adjustment, there was no statistically significant difference in survival between the LTG group and the OTG group (P=0.28 and P=0.34). CONCLUSIONS:LTG is safe and feasible to apply in stage 0-I gastric cancer. Comparing OTG, LTG with a similar overall complication rate and long-term survival, but reduce the incidence of OTG-related complications and does not increase the risk of LTG-related complications in stage 0-I gastric cancer. However, these findings still need to be confirmed in a large clinical trial.

INTRODUCTION:Assessing progress in cancer control at the national level is crucial, as it offers key insights into the overall effectiveness of the health system. Here, we aimed to describe 20-year trends in stage distribution, treatment patterns, and survival for gastric cancer in China, and to estimate stage- and treatment-specific 1-, 3-, 5-, and 10-year overall survival (OS) at the national level. METHODS:In this study, we included data from 40,158 patients diagnosed with gastric cancer between 1998 and 2022, derived from nine tertiary grade-A hospitals located across all four major regions of China. The characteristics, treatment modalities, and survival outcomes were analyzed across four predefined time periods: period 1 (1998-2005), period 2 (2006-2010), period 3 (2011-2015), and period 4 (2016-2022). Stage- and treatment-specific survival with 95 % confidence intervals (CIs) was estimated using the Kaplan-Meier method; differences were assessed by log-rank test. RESULTS:During the study period, there was an increasing proportion of patients with early stage gastric cancer from 9.8 % in 1998 to 19.5 % in 2022, while patients with metastatic disease remained stable. For early gastric cancer classified as cT1aN0, the proportion of patients undergoing endoscopic resection increased from 0.0 % in period 1-30.4 % in period 4. Among patients with locally advanced gastric cancer, the proportion receiving neoadjuvant therapy increased from 0.8 % to 17.3 %. Regarding survival outcomes, the 5-year OS rate of gastric cancer cohort increased from 38.2 % in period 1-46.1 % in period 4. Stage-specific 5-year OS rates were 90.0 % (stage I), 69.0 % (stage II), 37.0 % (stage III), and 13.7 % (stage IV). Compared with Japan, gastric cancer patients with stage IA in China exhibited higher 5-year OS rate (91.9 % vs. 89.6 %) but a much lower proportion (16.9 % vs. 43.6 %). Survival for stage IIIA-IIIC was poorer in China (48.5 % vs. 59.3 %, 34.7 % vs. 45.6 %, 21.8 % vs. 29.9 %; respectively). CONCLUSIONS:From 1998 to 2022, the proportion of patients diagnosed with early-stage gastric cancer in China gradually increased, and treatment strategies changed substantially over time, accompanied by a modest improvement in the 5-year OS rate. The disparities in stage distribution and survival outcomes between China and Japan highlight the need to further improve early detection of gastric cancer and to develop more effective treatment modalities for patients with stage III disease in China.

While numerous studies have reported that intratumor bacteria modulate tumor biological characteristics and therapeutic outcomes, the role of intracellular bacteria in gastrointestinal tumor (GIT) progression remains largely unexplored. Here, we show, through bioinformatics prediction and consecutive patient sample validation, that Stenotrophomonas is associated with tumor progression and poor prognosis in GIT. Using various murine tumor models, we find that intracellular Stenotrophomonas promotes GIT progression by decreasing IFNβ secretion and inhibiting MHC-II+ macrophages, thereby impairing the activity of effector CD8+ T cells. Mechanistically, Stenotrophomonas entry into tumor cells induces endoplasmic reticulum stress, degrades STING protein, and downregulates the type I IFN pathway response. Additionally, Stenotrophomonas contributes to resistance to immunotherapy in GIT, which can be reversed by levofloxacin. Our findings indicate that intracellular Stenotrophomonas within tumor cells plays an important role in promoting GIT progression and poor prognosis and could serve as a potential target to improve outcomes for patients with GIT. Bacteria can infect tumour cells which may affect the biological characteristics of the tumour or even the therapeutic outcome. Here authors show that Stenotrophomonas, upon entering tumour cells, trigger endoplasmic reticulum stress, leading to STING degradation and inhibition of MHC-II+ macrophages, which ultimately cause tumour progression and immunotherapy resistance.

Antiangiogenic therapies, such as bevacizumab, are among the causes of cancer-related death in patients with colorectal cancer (CRC) with liver metastasis. Delivering siRNAs via primary cell originating from primary cells is a promising method for targeting CRC liver metastasis and drug resistance. Here, it is found that the expression of CCL24 is significantly upregulated in tumor tissues at the CRC liver metastasis site. In addition, CCL24 is significantly upregulated in tumor tissues from bevacizumab-resistant patients. CCL24 promotes the formation of inflammatory tumor-associated fibroblast subsets in the CRC liver metastasis microenvironment and induces resistance to bevacizumab therapy. Based on these results, a primary cell-derived extracellular vehicle delivery system is designed for the simultaneous delivery of siRNAs targeting CCL24 in the tumor microenvironment (TME). Downregulation of CCL24 in the TME by delivering bioengineered extracellular vehicles significantly increased sensitivity to antiangiogenic therapy in a CRC mouse model. A novel therapeutic target is identified for patients with CRC with liver metastasis and suggested a possible therapeutic alternative for patients with CRC with resistance to antiangiogenic therapy and distant metastasis.

Stem-like CD8⁺ exhausted T cells (Tex) sustain antitumor immunity, whereas TGFβ signaling acts as a major immunosuppressive pathway. In patients with colorectal liver metastases, we observe that elevated TβRI expression in peri-metastatic hepatocytes correlates with poor prognosis. We therefore investigate whether disrupting hepatocytic TGFβ signaling can reinvigorate stem-like CD8⁺ Tex cells to restrict liver metastasis. In support of this hypothesis, mice with hepatocyte-specific TβRI depletion exhibit reduced liver metastatic burden across multiple tumor models. Mechanistically, hepatocytic TβRI blockade suppresses Galectin-9 secretion, which reshapes the transcriptional program of intra-tumoral CD8⁺ T cells. This reprogramming promotes a phenotypic transition from terminal exhaustion toward stem-like and effector states, yielding T cell subsets with enhanced metastasis-control capacity. Importantly, this axis functions independently of macrophages and CD4⁺ T cells. Furthermore, therapeutic delivery of Galunisertib using choline-modified lipid nanoparticles synergizes with αPD-1, fostering the conversion of exhausted CD8⁺ T cells into responsive Ly108⁺CX3CR1⁺ subsets and suppressing liver metastases. Collectively, our results identify hepatocyte TGFβ signaling as a targetable checkpoint against liver metastases.

Disulfidptosis is a unique type of programmed cell death that is distinct from previously known forms of cell death, such as pyroptosis, apoptosis, and necroptosis. Researchers have studied the significance of many forms of cell death in various diseases, particularly malignant tumors, in great detail in recent years. Therefore, how disulfidptosis affects colon cancer and how it functions in the immune system are unknown. Disulfidptosis-related gene (DRG) expression information was obtained from the TCGA-COAD cohort. Patients were categorized into two DRG groups using consensus cluster analysis, and the disulfidptosis-related differentially expressed genes (DRDEGs) were subsequently identified by differential analysis of the two clusters. Univariate Cox regression analysis of the DRDEGs was used to identify prognosis-related DEGs (PRDEGs). The screened PRDEGs were then subjected to LASSO-Cox regression analysis to determine the prognostic model on the basis of ten genes. Immunohistochemistry was used to verify the expression and prognostic value of marker genes. In the two DRG clusters, the characteristics of the tumor microenvironment (TME) significantly differed by the TME scores and infiltration levels of 23 human immune cell subpopulations. Prognostically meaningful risk scores were found, with a greater chance of mortality (p = 4.4e−7) for patients in the high-risk category. Furthermore, notable differences in TME scores, immune cell infiltration, and immune checkpoint expression were detected among the risk categories. The ROC curves revealed that the nomogram’s 1-, 2-, and 3-year AUCs were 0.75, 0.76, and 0.77, respectively, demonstrating the superior predictive capacity of the nomogram. Immunohistochemistry revealed that patients with high FABP4 and low ADAM8 and FSTL3 expressions had a better prognosis. The prognostic features based on 10 PRDEGs performed well in predicting survival, TME status, and response to immunity in COAD patients, helping provide personalized immunotherapy strategies for patients.

BACKGROUND:Type II diabetes mellitus (T2DM) has been associated with increased risk of colon cancer (CC) and worse prognosis in patients with metastases. The effects of T2DM on postoperative chemoresistance rate (CRR) and long-term disease-free survival (DFS) and overall survival (OS) in patients with stage III CC who receive curative resection remain controversial. AIM:To investigate whether T2DM or glycemic control is associated with worse postoperative survival outcomes in stage III CC. METHODS:This retrospective cohort study included 278 patients aged 40-75 years who underwent surgery for stage III CC from 2018 to 2021. Based on preoperative T2DM history, the patients were categorized into non-DM (n = 160) and DM groups (n = 118). The latter was further divided into well-controlled (n = 73) and poorly controlled (n = 45) groups depending on the status of glycemic control. DFS, OS, and CRR were compared between the groups and Cox regression analysis was used to identify risk factors. RESULTS:Patients in the DM and non-DM groups demonstrated similar DFS, OS, and CRR (DFS: 72.03% vs 78.75%, P = 0.178; OS: 81.36% vs 83.12%, P = 0.638; CRR: 14.41% vs 7.5%, P = 0.063). Poorly controlled DM was associated with a significantly worse prognosis and higher CRR than well-controlled DM (DFS: 62.22% vs 78.07%, P = 0.021; OS: 71.11% vs 87.67%, P = 0.011; CRR: 24.40% vs 8.22%, P = 0.015). High preoperative fasting plasma glucose [DFS: Hazard ratio (HR) = 2.684, P < 0.001; OS: HR = 2.105, P = 0.019; CRR: HR = 2.214, P = 0.005] and glycosylated hemoglobin levels (DFS: HR = 2.344, P = 0.006; OS: HR = 2.119, P = 0.021; CRR: HR = 2.449, P = 0.009) indicated significantly poor prognosis and high CRR, while T2DM history did not (DFS: HR = 1.178, P = 0.327; OS: HR = 0.933, P = 0.739; CRR: HR = 0.997, P = 0.581). CONCLUSION:Increased preoperative fasting plasma glucose and glycosylated hemoglobin levels, but not T2DM history, were identified as risk factors associated with poor postoperative outcomes and high CRR in patients with stage III CC.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has emerged as a promising therapeutic approach for treating advanced gastric cancer with peritoneal metastases. Herein, we conducted this meta-analysis to evaluate the feasibility, efficacy, and safety of PIPAC in this patient population. The literature between January 2011 and February 2024 was comprehensively searched on the following databases: PubMed, Embase, Web of Science, and the Cochrane Library. The search, guided by the Population-Intervention-Comparison-Outcome (PICO) framework, focused on studies reporting on the feasibility, efficacy, and safety of PIPAC. Data were pooled by using log transformation (PLN) or Freeman-Tukey double arcsine transformation. Of the 451 initially identified studies, 18 were included in the meta-analysis, comprising 671 patients who underwent 1,357 PIPAC procedures. Our data analysis indicated that 32.6% of the patients (95% confidence interval [CI], 23.5%-42.3%) completed three or more PIPAC procedures. Conversely, 2.3% of patients (95% CI, 0.6%-5%) either did not have access to or could not undergo PIPAC. The average rate of histological response across the included studies was 66.3% (95% CI, 59.1%-73.1%). Pooled results showed that 13.1% of patients (95% CI, 7.0%-20.7%) had reduced ascites after PIPAC, and 7.8% (95% CI, 4.8%-11.4%) became resectable. Adverse events were reported in 17.1% of patients (95% CI, 5.3%-33.4%), with 3.6% (95% CI, 1.4%-6.6%) experiencing severe adverse events (grade 3-5, Common Terminology Criteria for Adverse Events [CTCAE]). The pooled mortality related to PIPAC was 0.1% (95% CI, 0%-0.5%). The pooled proportions for 6-month, 1-year, and 2-year overall survival rates were 82.4% (95% CI, 69.2%-92.8%), 54.0% (95% CI, 45.7%-62.3%), and 20.0% (95% CI, 11.3%-30.3%), respectively. The average median overall survival was 11.7 months (95% CI, 9.3-14.0 months). Our study suggests that most patients can benefit from PIPAC treatment, such as improved quality of life and significantly longer median overall survival. Patients who received first-line chemotherapy prior to PIPAC and concomitant systemic chemotherapy during PIPAC treatment, and who underwent the PIPAC procedure on more than three occasions, exhibited a more favorable survival prognosis.

Stomach adenocarcinoma (STAD) with microsatellite instability (MSI) is associated with a better prognosis compared to Non-MSI. This study aims to elucidate the differences in the tumor microenvironment (TME) of MSI and explore its underlying mechanisms in STAD. TME differences between MSI and Non-MSI were analyzed using single-cell RNA sequencing (MSI = 7, Non-MSI = 19) and bulk RNA sequencing (MSI = 39, Non-MSI = 198). Differentially expressed genes (DEGs) were used to identify enriched pathways and hub genes. TNFSF9 expression was validated by immunohistochemistry (IHC) on 23 STAD sections (MSI = 13, Non-MSI = 10) and confirmed in tumor epithelial cells using SNU-1 (MSI) and AGS (Non-MSI) cell lines through quantitative polymerase chain reaction (qPCR) and Western blot (WB). The results showed MSI was significantly associated with a better prognosis (P < 0.05). Within the TME, MSI was associated with a higher abundance of antigen-presenting cells, including M1 macrophages (40.1

BACKGROUND:Accurate identification of tumor invasion depth and lymph node (LN) involvement in patients with colon cancer (CC) is critical for guiding treatment strategies. However, the preoperative prediction of tumor invasion depth and LN metastasis in CC remains challenging. As the intestinal tumor develops, the fat density in the mesentery increases. AIM:To investigate the efficacy of computed tomography (CT) value change in the mesentery contributed by the tumor (CT-T value) for predicting tumor invasion depth and LN metastasis. METHODS:Patients, who were diagnosed with CC and underwent surgery, were included and divided into the training and validation cohorts. CT-T values of the mesentery were extracted from the CT images. Cutoff points were determined using the receiver operating characteristic (ROC) curve, and the area under the ROC curve was employed to assess the performance of the CT-T value for tumor invasion depth and LN status prediction. RESULTS:Cutoff values of 11.83 and 17.17 were identified to discriminate T1/2 vs T3/4 and N0 vs N1/2, respectively. With a cutoff CT-T value of 11.83, the total diagnostic accuracy for T stage was 83.1% (81.5% for the training cohort and 86.2% for the validation cohort). With a cutoff CT-T value of 17.17, the total diagnostic accuracy for N stage was 77.3% (75.8% for the training cohort and 80.1% for the validation cohort), which was higher than that of CT-reported LN metastasis. CONCLUSION:In this study, we explored an efficient method for predicting preoperative T and N stages using the tumor-contributed CT value of the mesentery in CC, which displayed superior predictive accuracy.

BACKGROUND:Neoadjuvant chemoradiotherapy followed by radical surgery is the common treatment for patients with locally advanced rectal cancer. Presently, for patients with complete clinical response after neoadjuvant chemoradiotherapy, organ preservation ("watch-and-wait" and local excision strategies) has been increasingly favored. However, the optimal treatment for patients with complete clinical response remains unclear. OBJECTIVE:This study aimed to use Bayesian meta-analysis to determine the best treatment for patients with locally advanced rectal cancer with complete clinical response among radical surgery, local excision, and watch-and-wait strategies. DATA SOURCES:PubMed, Web of Science, Cochrane Library, and Embase (Ovid) databases were searched for literature published through December 31, 2023. STUDY SELECTION:Studies that compared 2 or more treatments for patients with complete clinical response were included. INTERVENTION:The analysis was completed via Bayesian meta-analysis using a random-effects model. MAIN OUTCOME MEASURES:Surgery-related complications, local recurrence, distant metastasis, and 5-year overall and disease-free survival rates. RESULTS:Eleven articles met the inclusion criteria. The watch-and-wait group and local excision group exhibited a higher rate of tumor recurrence compared to the radical surgery group (watch-and-wait vs radical surgery: OR, 9.10 [95% CI, 3.30-32.3]; local excision vs radical surgery: OR, 2.93 [95% CI, 1.05-9.95]). The distant metastasis, overall survival, and disease-free survival rates of the 3 treatments were not statistically different. The radical surgery group had the most number of stomas and had the greatest risk of morbidity than the watch-and-wait group (watch-and-wait vs radical surgery: OR, 0.00 [95% CI, 0.00-0.12]). LIMITATIONS:The study included only 1 randomized controlled trial compared to 10 observational studies, which could affect overall quality. Funnel plots of disease-free survival rates and stoma suggest significant publication bias among studies that compared radical surgery with the watch-and-wait strategy. CONCLUSIONS:The watch-and-wait strategy could be optimal for patients with locally advanced rectal cancer with complete clinical response after neoadjuvant chemoradiotherapy.

As one of the key metabolic enzymes in the glycolytic pathway, lactate dehydrogenase A (LDHA) might be linked to tumor proliferation by driving the Warburg effect. Circular RNAs (circRNAs) are widely implicated in tumor progression. Here, we report that circTATDN3, a circular RNA that interacts with LDHA, plays a critical role in proliferation and energy metabolism in CRC. We found that circTATDN3 expression was increased in CRC cells and tumor tissues and that high circTATDN3 expression was positively associated with poor postoperative prognosis in CRC patients. Additionally, circTATDN3 promoted the proliferation of CRC cells in vivo and vitro. Mechanistically, circTATDN3 was shown to function as an adaptor molecule that enhances the binding of LDHA to FGFR1, leading to increased LDHA phosphorylation and consequently promoting the Warburg effect. Moreover, circTATDN3 increased the expression of LDHA by sponging miR-511-5p, which synergistically promoted CRC progression and the Warburg effect. In conclusion, circTATDN3 may be a target for the treatment of CRC.

Background: Stomach adenocarcinoma (STAD) with microsatellite instability (MSI) have better prognosis compared with nonMSI. This study aims to elucidate the distinctions in the tumor microenvironment (TME) of MSI and explore its potential mechanisms in STAD. Methods: We analyzed TME differences between MSI and non-MSI using integrated single-cell RNA sequencing (N = 26) and bulk RNA sequencing (N = 237). Differentially expressed genes unveiled key pathways and hub genes, and TNFSF9 expression was validated through immunohistochemistry (IHC) quantitative polymerase chain reaction (qPCR) and Western blot analysis (WB). Results: The results demonstrated a significant association between MSI and improved prognosis (p < 0.05), along with a higher tumor mutation burden (p < 0.05). Our study revealed increased abundance of antigen-presenting cells (APCs) in MSI, including M1 cells (40.1% vs. 27.9%) and activated dendritic cells (22.1% vs. 10.5%). Signaling pathway and cell communication analyses indicated the enrichment of cytokine-related pathways in MSI. The findings further revealed an increased expression of TNFSF9 by tumor epithelial cells in MSI. Correlation analysis revealed a positive association between TNFSF9 expression and increased APC abundance. IHC, qPCR, and WB validation revealed increased TNFSF9 expression in MSI tumor epithelial cells. Conclusions: These results offer new insights into the TME in MSI, emphasizing the significant role of TNFSF9 in mediating MSI status, enhancing immunotherapy efficacy, and improving patient survival in STAD.

Background Tumor budding (TB) is a negative prognostic factor in colorectal cancer; however, its prognostic impact following neoadjuvant therapy for patients with rectal cancer remains unclear. This study aims to assess the prognostic impact of TB and the correlation between TB and other pathological features in patients with rectal cancer after neoadjuvant therapy. Methods A comprehensive search of PubMed, Embase, Cochrane, Scopus, CNKI, Wanfang, and ClinicalKey databases was conducted for studies on the prognosis of TB in rectal cancer after neoadjuvant therapy from the inception of the databases to January 2023, and the final literature included was determined using predefined criteria. Quality assessment of the studies included, extraction of general and prognostic information from them, and meta-analyses were carried out progressively. Results A total of 11 studies were included, and the results of the meta-analysis showed that high-grade tumor budding (TB-1) increased the risk of poor 5-year disease-free survival (HR = 1.75, 95% CI 1.38–2.22, P < 0.00001), 5-year overall survival (HR = 1.77, 95% CI 1.21–2.59, P = 0.003), local recurrence (OR = 4.15, 95% CI 1.47–11.75, P = 0.007), and distant metastasis (OR = 5.36, 95% CI 2.51–11.44, P < 0.0001) in patients with rectal cancer after neoadjuvant therapy. TB-1 was significantly associated with poor differentiation and lymphatic, perineural, and venous invasion. Conclusion Tumor budding is significantly correlated with unfavorable prognosis and poor pathological characteristics following neoadjuvant therapy for rectal cancer. We anticipate more high-quality, prospective studies in the future to confirm our findings. Systematic review registration PROSPERO CRD42022377564.

There is a paucity of confirmatory randomized controlled trials (RCTs) comparing the effectiveness of totally laparoscopic distal gastrectomy (TLDG) vs laparoscopy-assisted distal gastrectomy (LADG) for early gastric cancer (EGC). A phase III, prospective, multi-center RCT was conducted, wherein patients (n = 442) with clinical stage I gastric cancer eligible for laparoscopic distal gastrectomy were randomized 1:1 to the TLDG or the LADG group. Postoperative morbidity and quality of life (QoL) were compared. In total, 422 patients were assessed (TLDG, 216; LADG, 206) in the modified intention-to-treat (mITT) analysis. The morbidity rate did not differ significantly between the two groups (TLDG, 6.0

Adenocarcinoma of the esophagogastric junction (AEG) is a type of tumor that arises at the anatomical junction of the esophagus and stomach. Although AEG is commonly classified as a subtype of gastric adenocarcinoma (GAC), the tumor microenvironment (TME) of AEG remains poorly understood. To address this issue, we conducted single-cell RNA sequencing (scRNA-seq) on tumor and adjacent normal tissues from four AEG patients and performed integrated analysis with publicly available GAC single-cell datasets. Our study for the first time comprehensively deciphered the TME landscape of AEG, where heterogeneous AEG malignant cells were identified with diverse biological functions and intrinsic malignant nature. We also depicted transcriptional signatures and T cell receptor (TCR) repertoires for T cell subclusters, revealing enhanced exhaustion and reduced clone expansion along the developmental trajectory of tumor-infiltrating T cells within AEG. Notably, we observed prominent enrichment of tumorigenic cancer-associated fibroblasts (CAFs) in the AEG TME compared to GAC. These CAFs played a critical regulatory role in the intercellular communication network with other cell types in the AEG TME. Furthermore, we identified that the accumulation of CAFs in AEG might be induced by malignant cells through FGF-FGFR axes. Our findings provide a comprehensive depiction of the AEG TME, which underlies potential therapeutic targets for AEG patient treatment.

The success of immunotherapy for cancer treatment is limited by the presence of an immunosuppressive tumor microenvironment (TME); Therefore, identifying novel targets to that can reverse this immunosuppressive TME and enhance immunotherapy efficacy is essential. In this study, enrichment analysis based on publicly available single-cell and bulk RNA sequencing data from gastric cancer patients are conducted, and found that tumor-intrinsic interferon (IFN) plays a central role in TME regulation. The results shows that KDM3A over-expression suppresses the tumor-intrinsic IFN response and inhibits KDM3A, either genomically or pharmacologically, which effectively promotes IFN responses by activating endogenous retroviruses (ERVs). KDM3A ablation reconfigures the dsRNA-MAVS-IFN axis by modulating H3K4me2, enhancing the infiltration and function of CD8 T cells, and simultaneously reducing the presence of regulatory T cells, resulting in a reshaped TME in vivo. In addition, combining anti-PD1 therapy with KDM3A inhibition effectively inhibited tumor growth. In conclusions, this study highlights KDM3A as a potential target for TME remodeling and the enhancement of antitumor immunity in gastric cancer through the regulation of the ERV-MAVS-IFN axis.

BackgroundThere exists continuous controversy regarding the benefit of primary tumor resection (PTR) for stage IV colorectal cancer (CRC) patients. Little is known about how to predict the patients’ benefit from PTR. This study aimed to develop a tool for surgical benefit prediction.MethodsStage IV CRC patients diagnosed between 2010 and 2015 from the Surveillance, Epidemiology and End Results database were included. Patients receiving PTR who survived longer than the median cancer-specific survival (CSS) time of those who did not undergo PTR were considered to benefit from surgery. Logistic regression analysis identified prognostic factors influencing surgical benefit, based on which a nomogram was constructed. The data of patients who underwent PTR from our institution was used for external validation. A user-friendly webserver was then built for convenient clinical use.ResultsThe median CSS of the PTR group was 23 months, significantly longer than that of the non-PTR group (7 months, P < 0.001). In the PTR group, 23.3% of patients did not benefit from surgery. Logistic regression analysis identified age, marital status, tumor location, CEA level, chemotherapy, metastasectomy, tumor size, tumor deposits, number of examined lymph nodes, N stage, histological grade and number of distant metastases as independently associated with surgical benefit. The established prognostic nomogram demonstrated satisfactory performance in both the internal and external validation.ConclusionPTR was associated with prolonged CSS in stage IV CRC. The proposed nomogram could be used as an evidenced-based platform for risk-to-benefit assessment to select appropriate patients for undergoing PTR.

AimsTo investigate the potential functions and mechanisms of tumourigenesis in carboxypeptidase E (CPE) and its prognostic value in gastric cancer, and to develop a predictive model for prognosis based on CPE.ResultsTranscriptome level variation and the prognostic value of CPE in different types of cancers were investigated using bioinformatics analyses. The association between CPE and clinicopathological characteristics was specifically explored in gastric cancer. Elevated CPE expression was associated with poor survival and recurrence prognosis and was found in cases with a later clinical stage of gastric cancer. The CPE was considered an independent prognostic factor, as assessed using Cox regression analysis. The prognostic value of CPE was further verified through immunohistochemistry and haematoxylin staining. Enrichment analysis provided a preliminary confirmation of the potential functions and mechanisms of CPE. Immune cell infiltration analysis revealed a significant correlation between CPE and macrophage infiltration. Eventually, a prognosis prediction nomogram model based on CPE was developed.ConclusionCPE was identified as an independent biomarker associated with poor prognosis in gastric cancer. This suggests that CPE overexpression promoted epithelial-mesenchymal transition via the activation of the Erk/Wnt pathways, leading to proliferation, invasion, and metastasis. Targeted therapeutic strategies for gastric cancer may benefit from these findings.