Gastric cancer (GC) is an aggressive and heterogeneous disease with poor survival outcomes. The progression of GC involves complex, multi-step processes. Endothelial cells (ECs) play a crucial role in tumor angiogenesis, proliferation, invasion, and metastasis, particularly through the process of endothelial-to-mesenchymal transition (EndoMT). However, the specific role and mechanisms of EndoMT in gastric cancer remain unclear. Based on 6 GC single-cell RNA-sequencing (scRNA-seq) cohorts (samples = 97), we established an EndoMT-related gene signature, termed EdMTS. Leveraging this gene signature, ssGSEA was applied to calculate sample scores across multiple bulk RNA-seq datasets, which include information on immunotherapy, metastasis, GC progression, and survival. Moreover, we applied the Monocle2 method to calculate cell pseudotime and used CellChat to analyze interactions between malignant and EC cells. We verified the molecular mechanism by multiple immunofluorescence and cell function experiments. Findings In this study, we established a single-cell atlas of ECs in GC and identified a subpopulation of COL1A1+ ECs that play a critical role in tumor progression and metastasis. These COL1A1+ ECs were significantly associated with worse clinical outcomes in GC patients. Further analysis revealed that COL1A1+ ECs originated from lymphatic ECs and underwent EndoMT through the upregulation of CEBPB, driving tumor invasiveness. Moreover, COL1A1+ ECs interacted with malignant cells via ANGPTL4-SDC4 axis, enhancing invasion and migration. These findings provide a deeper understanding of the role of COL1A1+ ECs in GC progression and highlight potential therapeutic targets for disrupting the EndoMT process in these cells to provide a benefit for GC patients.

In human beings heterogenous, pervasive and lethal malignancies of different parts of the gastrointestinal (GI) tract viz., tumours of the oesophagus, stomach, small intestine, colon, and rectum, represent gastrointestinal malignancies. Primary treatment modality for gastric cancer includes chemotherapy, surgical interventions, radiotherapy, monoclonal antibodies and inhibitors of angiogenesis. However, there is a need to improve upon the existing treatment modality due to associated adverse events and the development of resistance towards treatment. Additionally, age has been found to contribute to increasing the incidence of tumours due to immunosenescence-associated immunosuppression. Immunosenescence is the natural process of ageing, wherein immune cells as well as organs begin to deteriorate resulting in a dysfunctional or malfunctioning immune system. Accretion of senescent cells in immunosenescence results in the creation of a persistent inflammatory environment or inflammaging, marked with elevated expression of pro-inflammatory and immunosuppressive cytokines and chemokines. Perturbation in the T-cell pools and persistent stimulation by the antigens facilitate premature senility of the immune cells, and senile immune cells exacerbate inflammaging conditions and the inefficiency of the immune system to identify the tumour antigen. Collectively, these conditions contribute positively towards tumour generation, growth and eventually proliferation. Thus, activating the immune cells to distinguish the tumour cells from normal cells and invade them seems to be a logical strategy for the treatment of cancer. Consequently, various approaches to immunotherapy, viz., programmed death ligand-1 (PD-1) inhibitors, Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors etc are being extensively evaluated for their efficiency in gastric cancer. In fact, PD-1 inhibitors have been sanctioned as late late-line therapy modality for gastric cancer. The present review will focus on deciphering the link between the immune system and gastric cancer, and the alterations in the immune system that incur during the development of gastrointestinal malignancies. Also, the mechanism of evasion by tumour cells and immune checkpoints involved along with different approaches of immunotherapy being evaluated in different clinical trials will be discussed.

Epstein-Barr virus (EBV)-associated gastric cancers (EBVaGCs) account for about 10% of gastric cancers globally, with higher prevalence in East Asia and Latin America. These cancers develop through a "gastritis-infection-cancer sequence" and are characterized by unique molecular signatures, including CpG island methylator phenotype and mutations in ARID1A and PIK3CA genes. EBVaGCs typically present in the proximal stomach with diffuse-type histology and dense lymphocytic infiltration. Key viral proteins EBNA1 and LMP2A drive oncogenesis by altering cellular processes and immune responses. The IFN-γ signature and extensive epigenetic modifications contribute to their distinct profile. Despite often presenting at advanced stages, EBVaGCs generally have a more favorable prognosis. EBV employs sophisticated strategies to evade immune detection, utilizing latent proteins and noncoding RNAs. Paradoxically, despite an immune-hot environment, EBVaGCs demonstrate effective immune evasion, partly due to the expression of immune checkpoint molecules like PD-L1 and LAG3. Treatment approaches vary based on disease stage, from endoscopic resection for early-stage cancers to systemic therapies for advanced cases. Immunotherapy, particularly PD-1/PD-L1 inhibitors, shows promising results. Emerging research suggests combining these with LAG3 inhibitors may enhance efficacy. Ongoing research and advanced genomic techniques continue to reveal new insights, paving the way for personalized therapies and novel diagnostic approaches.

Background: Long non-coding RNAs (lncRNAs) are crucial factors affecting the occurrence, progression, and prognosis of gastric carcinoma (GC). The accumulation of disulfide bonds to excessive levels in cells expressing high SLC7A11 triggers disulfidptosis, which functions as a regulated form of cellular death. Research has demonstrated that upregulated SLC7A11 is common in human cancers, but the effect of disulfidptosis on GC remains unclear. Identifying lncRNAs associated with disulfidptosis (drlncRNAs) and establishing a prognostic risk profile holds considerable importance for advancing GC research and treatment. Methods: Clinical records and transcriptomic datasets from individuals with GC were acquired from The Cancer Genome Atlas (TCGA) repository. A three-drlncRNA risk model was built using three common regression analysis methods. Then we used receiver operating characteristic (ROC) curves, independent prognostic analysis, and additional statistical approaches to assess the precision of the model. This investigation additionally encompassed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, immune cell infiltration evaluation, and pharmacological sensitivity predictions. To further investigate immunotherapy response disparities between patient cohorts with elevated- and reduced-risk scores, analyses of tumor mutational burden (TMB), tumor immune dysfunction and exclusion (TIDE), and microsatellite instability (MSI) were implemented. Results: We constructed a unique model composed of three drlncRNAs (AC107021.2, AC016394.2, and AC129507.1). Its independent prognostic capability for GC patients was validated through both single-variable and multivariable Cox regression analyses. GO and KEGG pathway assessments revealed predominant enrichment within the elevated-risk cohort, particularly in pathways involving sulfur compound interactions, traditional Wnt signaling mechanisms, cell-substrate adherens junctions, and cAMP signaling cascades, among others. Tumor microenvironment (TME) evaluation demonstrated elevated ImmuneScores, StromalScores, and ESTIMATEScores within the high-risk patient population. Concurrently, this elevated-risk cohort exhibited enhanced immune cell infiltration patterns, whereas the reduced-risk group displayed superior expression of immune checkpoints (ICPs). Additional investigations revealed that patients categorized into the reduced-risk classification possessed greater tumor mutational burden, increased MSI-high proportions, and diminished tumor immune dysfunction and exclusion scores compared to their high-risk counterparts. Pharmacological sensitivity assessments confirmed the superior efficacy of several therapeutic agents, including gemcitabine and veliparib (ABT.888), in patients with lower risk classifications. Conclusions: Our established risk stratification system demonstrates independent prognostic predictive capacity while offering personalized clinical intervention guidance for individuals diagnosed with GC.

The year 2024 marks the 60th anniversary of the discovery of the Epstein-Barr virus (EBV), the first virus confirmed to cause human cancer. Viral infections significantly contribute to the global cancer burden, with seven known Group 1 oncogenic viruses, including hepatitis B virus (HBV), human papillomavirus (HPV), EBV, Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV), human T-cell leukemia virus type 1 (HTLV-1), and human immunodeficiency virus (HIV). These oncogenic viruses induce cellular transformation and cancer development by altering various biological processes within host cells, particularly under immunosuppression or co-carcinogenic exposures. These viruses are primarily associated with hepatocellular carcinoma, gastric cancer, cervical cancer, nasopharyngeal carcinoma, Kaposi sarcoma, lymphoma, and adult T-cell leukemia/lymphoma. Understanding the mechanisms of viral oncogenesis is crucial for identifying and characterizing the early biological processes of virus-related cancers, providing new targets and strategies for treatment or prevention. This review first outlines the global epidemiology of virus-related tumors, milestone events in research, and the process by which oncogenic viruses infect target cells. It then focuses on the molecular mechanisms by which these viruses induce tumors directly or indirectly, including the regulation of oncogenes or tumor suppressor genes, induction of genomic instability, disruption of regular life cycle of cells, immune suppression, chronic inflammation, and inducing angiogenesis. Finally, current therapeutic strategies for virus-related tumors and recent advances in preclinical and clinical research are discussed.

Identifying predictive biomarkers for immune checkpoint inhibitor (ICI) treatment is critical for gastric cancer (GC) prognosis. C-X-C motif chemokine ligand 13(CXCL13) plays an important role in immune regulation by binding exclusively to its receptor CXCR5. However, its role, underlying mechanisms, and prognostic significance in ICI-treated GC patients remain controversial.

This study investigated the clinical significance of CXCL13 and its potential immunomodulatory function in GC patients. A total of 144 GC patients from two cohorts, who received a combination of chemotherapy and anti-PD-1 antibody, were analyzed. The expression of CXCL13 was assessed using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay. Associations between CXCL13, CXCR5, CD8, and CD4 were assessed by IHC and immunofluorescence. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards model. The treatment response to CXCL13 and anti-PD-1 antibody was investigated using a subcutaneous xenograft tumor mouse model.

The results suggested that patients with high CXCL13 expression had prolonged survival. High CXCL13 expression exhibited increased infiltration of CXCR5+CD8+ T cells and was associated with better outcomes. The combined assessment of CXCL13, CXCR5, and CD8+ T cells served as an independent predictor of prognosis. Additionally, CXCR5 and CD8+ T cells were enriched in tertiary lymphoid structures (TLSs), which conferred a prognostic benefit in the presence of high CXCL13 expression. CXCL13, in combination with anti-PD-1 therapy, retarded tumor growth in vivo, resulting in increased infiltration of CXCR5+CD8+ T cells.

This study identified CXCL13 as a prognostic factor in GC patients receiving ICI therapy, emphasizing its critical role in the antitumor microenvironment via CXCR5+CD8+ T cells.

Gastric cancer (GC) represents a global health-care challenge. Recent progress in immunotherapy has elicited attracted considerable attention as a viable treatment option through modulating the host immune system and unleashing pre-existing immunity, which has profoundly revolutionized oncology, especially GC. Nonetheless, low clinical response and intrinsic and acquired resistance remain persistently challenging. The microenvironment of GC comprising multifarious stromal cell types has remarkable immunosuppressive elements that may impact the efficacy of immunotherapy. Immunosenescence is increasingly regarded as a factor that contributes to cancer development, remodels the tumor microenvironment and affects the efficacy of immunotherapy. Natural products are at the forefront of traditional medicine. Senotherapeutics is a class of drugs and natural products capable of delaying, preventing, or reversing the senescence process (i.e., senolytics) or suppressing senescence-associated secretory phenotype (i.e., senomorphics). Emerging evidence supports that natural products can improve the efficacy of existing immunotherapy and expand their indications in GC mainly based upon remodeling the immunosuppressive microenvironment and reversing immunosenescence. The review provides an integrated review of previously reported and ongoing clinical trials with immunotherapeutic regimens in GC and discusses current challenges. Next, we focus on natural compounds that exert anti-GC functions and possess immunomodulatory properties. More attention is paid to the potential of these natural compounds in modulating the immune microenvironment and immunosenescence. Lastly, we discuss the nanomedicine that can overcome the deficiencies of natural products. Altogether, our review suggests the enormous potential of natural compounds in GC immunotherapy, and provides an important direction for future research.

To evaluate the efficacy and safety of adding toripalimab to bevacizumab and platinum-based chemotherapy as first-line treatment for refractory recurrent or metastatic (R/M) cervical cancer (CC).

Patients were administered toripalimab (240 mg) + bevacizumab (7.5 mg/kg) combined with platinum-based chemotherapy once every three weeks for six cycles, followed by the maintenance therapy involving toripalimab + bevacizumab once every 3 weeks for 12 months or when disease progression or intolerable toxicity occurred. The primary endpoint was the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were safety profiles, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

Twenty-four patients were enrolled in this study and in the final analysis. The median follow-up duration was 18.6 (range, 3.3-28.5) months. The ORR was 83.3% (95% confidence interval [CI]=62.6-95.3) and the DCR was 95.8% (95% CI=78.9-99.9); 9 (37.5%) patients achieved complete response, 11 (45.8%) achieved partial response, and 3 (12.5%) had stable disease. The median PFS was 22.6 (95% CI=10.4-34.7) months and the median OS was not reached. The most common grade 3 treatment-related adverse events (AEs) were neutropenia (41.7%) and leukopenia (16.7%). The most common immune-related AEs (irAEs) were thyroid dysfunction (37.5%) and increased adrenocorticotropic hormone (37.5%) and serum cortisol levels (33.3%). No grade ≥3 irAEs were observed.

Toripalimab combined with bevacizumab and platinum-based chemotherapy show promising clinical efficacy and favorable safety profile, providing an alternative first-line treatment option for patients with R/M CC.

ClinicalTrials.gov Identifier: NCT04973904.

Gastric cancer (GC), one of the most prevalent malignancies worldwide, is distinguished by extensive genetic and phenotypic heterogeneity, posing persistent challenges to conventional diagnostic and therapeutic strategies. The significant global burden of GC highlights an urgent need to unravel its complex underlying mechanisms, discover novel diagnostic and prognostic biomarkers, and develop more effective therapeutic interventions. In this context, this review comprehensively examines the transformative roles of cutting-edge technologies, including radiomics, pathomics, genomics, transcriptomics, epigenomics, proteomics, and metabolomics, in advancing precision diagnosis and treatment for GC. Multiomics data analysis not only deepens our understanding of GC pathogenesis and molecular subtypes but also identifies promising biomarkers, facilitating the creation of tailored therapeutic approaches. Additionally, integrating multiomics approaches holds immense potential for elucidating drug resistance mechanisms, predicting patient outcomes, and uncovering novel therapeutic targets, thereby laying a robust foundation for precision medicine in the comprehensive management of GC.

More than 90% of advanced gastric cancers (GC) are microsatellite-stable (MSS). Compared to the high response rate of immune checkpoint inhibitors (ICI) in microsatellite-instability-high (MSI-H) GCs, only 10% of unstratified MSS GCs respond to ICIs. In this study, we apply semi-supervised learning to stratify potential ICI responders in MSS GCs, achieving high accuracy, quantified by an area under the curve of 0.924. Spatial analysis of the tumor microenvironment of ICI-sensitive GCs reveals a high level of T-bet+ CD8 + T cell infiltration in their tumor compartments. T-bet+ CD8 + T cells exhibit superior anti-tumor activity due to their increased ability to infiltrate tumors and secrete cytotoxic molecules. Adoptive transfer of T-bet+ CD8 + T cells boosts anti-tumor immunity and confers susceptibility to ICIs in immune-ignorant MSS GCs in a humanized mouse model. Spatial RNA sequencing suggests a positive-feedback loop between T-bet+ T cells and PD-L1+ tumor cells, which eventually drives T cell exhaustion and can therefore be leveraged for ICI therapy. In summary, our research provides insights into the underlying mechanism of anti-tumor immunity and deepens our understanding of varied ICI responses in MSS GCs.

One of the most prevalent malignant tumors worldwide, stomach cancer still has a high incidence and fatality rate in China, and the number of young people developing early-onset gastric cancer is steadily increasing. The 5-year survival rate of stomach cancer is typically 30%-35%, the prognosis is bad, the patients' quality of life is low, and the progression of advanced gastric cancer cannot be effectively managed despite the use of surgical surgery, chemotherapy, and other medicines. We urgently need molecular biomarkers with high specificity and sensitivity to increase the early gastric cancer detection rate, extend patient survival, and improve patient quality of life. The initial diagnosis of gastric cancer primarily depends on gastroscopy and biopsy, and invasive procedures cause significant discomfort to patients. Similar to this, treating advanced and metastatic stomach cancer is a pressing issue that requires attention. More and more immune checkpoint molecules have been discovered, and corresponding inhibitors are gradually being applied to clinical diagnosis and treatment. Recently, some non-coding RNAs have begun to be used as new targets for the treatment of gastric cancer. Some non-coding RNAs are highly present in the serum or urine of gastric cancer patients and can be used as diagnostic markers or prognostic indicators. Many clinical trials targeting non-coding RNAs have also shown good therapeutic effects. In general, targeting non-coding RNAs has shown good therapeutic effects. The biomarkers for gastric cancer detection and treatment are reviewed in this article, focusing on the new non-coding RNAs used in diagnosis, prognosis, and treatment. Patients with stomach cancer should have access to more precise and efficient diagnosis and treatment choices as a result of ongoing technological advancements and thorough research.

Our team previously reported that MACC1 levels are closely related to a variety of tumors and the efficacy of immune checkpoint blockade (ICB) therapy. However, the predictive value of MACC1 levels for lung adenocarcinoma (LUAD) immunotherapy has not been studied. This study aimed to investigate the predictive effect of the oncogene MACC1 on ICB reactivity in patients with LUAD. First, the expression patterns and clinical features of MACC1 in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were comprehensively evaluated using R packages. We subsequently assessed the correlations between MACC1 and immunological characteristics in the LUAD tumor microenvironment (TME) using the CIBERSORT algorithm. The results revealed that MACC1 overexpression was significantly correlated with 3 immune checkpoints, 14 tumor-infiltrating immune cells (TIICs), 9 immunomodulators, 5 anticancer immune process activities, and 3 effector genes of TIICs in LUAD. Additionally, on the basis of the prognostic genes from LASSO analysis, we developed the MACC1-related Risk Score (MRRS), which can accurately predict the prognosis and response to cancer immunotherapy in LUAD patients (HR = 3.50, AUC at 1, 2, and 3 years = 0.737, 0.744, and 0.724, respectively). Finally, in vivo experiments revealed that the combination of MACC1 silencing and PD-L1 inhibitors significantly inhibits tumor progression. These findings increase our understanding of MACC1 as a potential prognostic biomarker and potential therapeutic target for cancer immunotherapy. The MRRS may play a critical role in predicting the response of LUAD patients to ICB therapy.

Leucine-rich repeat containing 25 (LRRC25) is distinguishingly expressed in different tumor types, but the relationship with immune cell infiltration in gastric cancer stills unclear. We analyzed LRRC25 expression using pan-cancer data from The Cancer Genome Atlas and gene data from Gene Expression Omnibus. The clinical significance was further evaluated using gastric cancer tissues derived from clinical trials (no. NCT04208347).

Through bioinformatics analysis of TCGA database and the UCSC Xena database, we found the correlation between LRRC15, gastric cancer, and immune cell infiltration. Further, multiplex immunohistochemistry/immunofluorescence (mIHC/IF), tissue microarray, and image acquisition and quantitative analysis confirmed our theory.

It was discovered that LRRC25 was highly expressed in gastric cancer. Further analysis revealed that the expression of LRRC25 associated with gene sets implicated in immunity, including those in innate immunity, adaptive immunity, and chemokine signaling pathways. The result of (mIHC/IF) suggests a negative relevance between LRRC25 and response of anti-PD-1 treatment and reveals a trend of consistent change on LRRC25 + cells and CD16 expression. We also discovered that LRRC25 expression significantly associated with immune cell infiltration level. In particular, there is a relationship between LRRC25 and the phenotype and function of NK cells.

High LRRC25 expression contributes to immunosuppressive microenvironment by influencing chemokine axis in gastric cancer. LRRC25 may serve as a clinically useful biomarker for predicting neoadjuvant immunotherapeutic response in patients with gastric cancer. LRRC25 can affect the phenotype and function of NK cells.

To investigate the cost-effectiveness of toripalimab plus chemotherapy versus chemotherapy alone for advanced non-small cell lung cancer (NSCLC) patients from a societal perspective.

A partitioned-survival model estimated the costs and cost-effectiveness of toripalimab plus chemotherapy versus standard chemotherapy for advanced NSCLC over 20 years. Clinical data were derived from the CHOICE-01 trial, and cost and utility inputs were gathered from Yaozh.com, expert interviews, and a nationwide hospital-based survey. Costs were reported in 2022 US dollars, and outcomes included quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs), with a 5% discount rate was applied. Sensitivity, subgroup, and scenario analyses verified the robustness of results.

Toripalimab plus chemotherapy resulted in 3.048 QALYs and a total cost of $60,813, with an ICER of $19,066 per QALY gained, below China's 3 times GDP per capita threshold ($38,223). Robustness is confirmed through sensitivity, subgroup and scenario analyses.

Toripalimab plus chemotherapy is a cost-effective option for treatment-naive advanced NSCLC compared to chemotherapy alone, providing valuable evidence for clinical and reimbursement decision-making.

Gastric cancer remains one of the most prevalent and lethal malignancies worldwide, characterized by poor survival rates, particularly in advanced stages. In recent years, a paradigm shift in gastric cancer treatment has been witnessed with the introduction of immunotherapy and targeted therapies. This review provides a detailed examination of current immunotherapeutic strategies, including adoptive cell therapy (ACT), immune checkpoint inhibitors (ICIs), and cancer vaccines. Additionally, it explores advancements in targeted therapies, focusing on the human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor receptor (VEGFR) signaling pathways, as well as emerging targets such as claudin 18.2. Clinical trials investigating chimeric antigen receptor T-cell (CAR-T) therapy, T-cell receptor-engineered T-cell (TCR-T) therapy, and natural killer (NK) cell-based treatments have shown promise, particularly when combined with conventional chemotherapeutic regimens. However, challenges such as cytokine release syndrome, immune-related toxicities, and scalability issues remain significant. The combination of immunotherapy with targeted therapies represents a promising approach to enhance treatment outcomes. Future directions emphasize the need to overcome resistance mechanisms and refine treatment strategies to improve efficacy while reducing adverse effects. This review aims to elucidate the current landscape of immunotherapy and targeted therapy in gastric cancer and to explore their potential in shaping the future of clinical management for this devastating disease.

Immunotherapy has improved survival in patients with advanced hepatocellular carcinoma (HCC); yet, objective radiological responses occur in only about 20% of cases, suggesting variable benefits. This study aimed to identify serologic markers predictive of response to immune checkpoint inhibitors (ICIs). A cohort of 38 advanced HCC patients receiving immunotherapy was prospectively analyzed. Levels of cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), and cytokines were measured pre-treatment and three months post-treatment initiation. Genomic profiling of ctDNA was also conducted. Baseline levels of cfDNA and ctDNA effectively discriminated HCC patients based on their radiological response to ICIs. Additionally, individuals with pathologic mutations in the CDKN2A gene exhibited significantly reduced survival. Patients with progressive disease (PD) as their best radiological response had significantly fewer copy number variations (CNVs) than those with a radiological response. Furthermore, levels of IL10, PD1, and TGFβ assessed after three months of treatment showed significant variations correlating with survival status. In conclusion, the analysis of cfDNA, ctDNA, and cytokines may improve treatment selection for HCC patients by predicting their expected response to immunotherapies.

To systematically evaluate the efficacy and safety of combination therapy with toripalimab in the treatment of advanced gastric cancer (GC).

We conducted a thorough search for relevant studies in PubMed, Embase, Cochrane Library, and Web of Science. Effect estimates were computed utilizing Stata software (version 14.0) and either random or fixed effects models, as applicable. A subgroup analysis was undertaken to assess the effect of various combination therapies on overall response rate (ORR). Begg and Egger's tests were employed to assess publication bias.

The study consisted of 8 trials, which included 277 participants with advanced gastric cancer. The overall ORR was 41.4% (95% CI, 32.4%-50.3%), with a disease control rate (DCR) of 83.6% (95% CI, 74.6%-92.7%), a median overall survival (mOS) of 11.0 months (95% CI, 9.6-12.4), and a median progression-free survival (mPFS) of 4.2 months (95% CI, 2.5-6.0) for the combination therapy with toripalimab. Subgroup analysis revealed that the combination of toripalimab and chemotherapy achieved a greater ORR compared to the non-chemotherapy group, with ORR rates of 49.8% (95% CI, 42.2%-57.4%) and 31.9% (95% CI, 26.7%-37.1%), respectively. The combination therapy with toripalimab led to adverse events (AEs) of any grade at 94.0% of cases (95% CI, 89.5%-98.5%) and grade 3 AEs at 32.4% (95% CI, 17.8%-47.1%). The sensitivity analysis indicated that no single study affected the overall results.

Combination therapy of toripalimab can improve clinical efficacy, although with increased but manageable toxicity. Additional clinical trials are required to assess comprehensively the efficacy and safety of alternative toripalimab regimens. The review agreement has been recorded with PROSPERO (CRD42024585696).

Cancer remains a significant public health issue worldwide, standing as a primary contributor to global mortality, accounting for approximately 10 million fatalities in 2020 [...].

The aim of the present study is to report the clinical results of patients with advanced intrahepatic cholangiocarcinoma (ICC) who received combination therapy of hepatic arterial infusion chemotherapy (HAIC), toripalimab and surufatinib.

The study cohort consisted of 28 patients with advanced ICC who were treated with HAIC (mFOLFOX6 regimen, Q3W) in combination with intravenous toripalimab (240 mg, Q3W) and oral surufatinib (150 mg, once daily). The cohort had 14 male and 14 female patients. The baseline characteristics of the study cohort were obtained. The tumor response and drug-associated toxicity were assessed and reported.

During the follow-up period (median follow-up time: 11.3 months; range: 4-19 months), four patients died of tumor progression. The objective response rate and disease control rate were 58% and 79%, respectively. The mPFS was 9.5 months, and the overall survival rate was 83.3%. The most frequent adverse events were nausea and vomiting (100%) and abdominal pain (85.7%). Serious complications related to death were not observed.

The combination treatment schedule for advanced ICC demonstrated positive efficacy and safety profiles.

This study provides promising clinical guidance for the treatment of advanced cholangiocarcinoma and is expected to modify the treatment strategy for this disease.

This study investigated the expression pattern of Vesicular Amine Transporter 1 (VAT1) in gastric cancer (GC) and its impact on prognosis, alongside evaluating its potential as a biomarker for immunotherapy and chemotherapy. Analysis of transcriptomic data, supported by experimental validation, revealed that VAT1 is highly expressed in GC and is associated with poor prognosis. Kaplan-Meier and ROC analyses demonstrated VAT1's potential in GC diagnosis, while multivariate analysis confirmed its role as an independent risk factor. Gene set enrichment analysis indicated that VAT1 plays a role in regulating the MAPK signaling pathway and epithelial-mesenchymal transition (EMT) in GC. Immune infiltration analysis showed a positive correlation between VAT1 and immune cells, particularly macrophages, and a negative correlation with chemotherapy sensitivity. In vitro and in vivo experiments further confirmed VAT1's critical role in promoting GC cell proliferation and inhibiting apoptosis. Overall, VAT1 holds significant value not only in GC diagnosis and prognosis but also as a potential target for immunotherapy and overcoming drug resistance.

The administration of second-line or subsequent immune checkpoint inhibitors (ICIs) in previously treated patients with advanced solid cancers has been clinically investigated. However, previous clinical trials lacked an appropriate primary endpoint for efficacy assessment. This systematic review aimed to explore the most optimal early efficacy endpoint for such trials.

Phase 2 or 3 clinical trials involving patients with advanced solid cancers with disease progression following standard first-line therapy receiving second-line or subsequent ICI administration, with adequate survival outcome data, were included from PubMed, Embase, Web of Science, and Cochrane Library databases before February 2023. Quality assessment was conducted using the Cochrane tool and Newcastle-Ottawa Quality Assessment Scale for Cohort Studies for randomized controlled trials (RCTs) and non-randomized trials, respectively. Objective response rate (ORR) and progression-free survival (PFS) at 3, 6, and 9 months were investigated as potential early efficacy endpoint candidates for 12-month overall survival (OS), with a strong correlation defined as Pearson's correlation coefficient r ≥ 0.8.

A total of 64 RCTs comprising 22,725 patients and 106 non-randomized prospective trials involving 10,608 participants were eligible for modeling and external validation, respectively. RCTs examined 15 different cancer types, predominantly non-small-cell lung cancer (NSCLC) (17, 28%), melanoma (9, 14%), and esophageal squamous cell carcinoma (5, 8%). The median sample size of RCTs was 124 patients, and the median follow-up time was 3.2-57.7 months. The ORR (r = 0.38; 95% confidence interval [CI], 0.18-0.54) and PFS (r = 0.42; 95% CI, 0.14-0.64) exhibited weak trial-level correlations with OS. Within ICI treatment arms, the r values of ORR and 3-, 6-, and 9-month PFS with 12-month OS were 0.61 (95% CI, 0.37-0.79), 0.78 (95% CI, 0.62-0.88), 0.84 (95% CI, 0.77-0.90), and 0.86 (95% CI, 0.79-0.90), respectively. External validation of 6-month PFS indicated an acceptable discrepancy between actual and predicted 12-month OS.

In non-randomized phase 2 trials on second-line or subsequent ICI therapy in patients with advanced solid cancers, 6-month PFS could serve as an early efficacy endpoint. However, early efficacy endpoints are not recommended in RCTs to replace OS.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited treatment options in advanced stages. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting PD1/PD-L1, has emerged as a promising therapeutic approach. However, a significant proportion of patients exhibit primary or acquired resistance, limiting the overall efficacy of immunotherapy. This review provides a comprehensive analysis of the mechanisms underlying immunotherapy resistance in GC, including the role of the tumor immune microenvironment, dynamic PD-L1 expression, compensatory activation of other immune checkpoints, and tumor genomic instability. Furthermore, the review explores GC-specific factors such as molecular subtypes, unique immune evasion mechanisms, and the impact of Helicobacter pylori infection. We also discuss emerging strategies to overcome resistance, including combination therapies, novel immunotherapeutic approaches, and personalized treatment strategies based on tumor genomics and the immune microenvironment. By highlighting these key areas, this review aims to inform future research directions and clinical practice, ultimately improving outcomes for GC patients undergoing immunotherapy.

Synchronous multiple primary lung cancer (sMPLC) exhibits distinct histopathological characteristics among pulmonary nodules. However, a comprehensive understanding of the somatic mutation landscape and transcriptome heterogeneity is lacking. Therefore, our study aims to meticulously investigate genomic distinctions among multiple pulmonary nodules within individual patients.

We performed targeted DNA sequencing on tumor specimens and conducted bulk RNA transcriptome analysis on 53 multiple nodules originating from 26 lung cancer patients. The multiple nodules from the same patient was determined as major nodule and minor nodule. Additionally, the tumor tissues underwent histopathological evaluation through H&E staining, complemented by a comprehensive series of immunohistochemistry (IHC) analyses to detect protein expression. The detected protein markers encompassed PD-L1, Ki67, and others.

For the 53 nodule samples from 26 MPLCs patients, EGFR was the mostly mutated genes, and the TP53 mutation frequency was notably different between major and minor nodules. Furthermore, pathway enrichment analysis based on the differentially expressed genes (DEGs) between major and minor nodules revealed the significantly active cell cycle and p53 pathways in the major nodules. Additionally, both major and minor nodules demonstrated mostly similar immune microenvironment and PD-L1 protein expression, and a significantly higher expression of Ki67. A noteworthy suppression was observed in the immune microenvironment in nodules, revealed by the expression of macrophage, neutrophils, and NK cells. Furthermore, minor nodules exhibited a modestly elevated expression of macrophages compared to major nodules. Additionally, among the significantly up-regulated cell cycle-related genes in the major nodules when compared with minor nodules, CCNE1 mRNA expression demonstrated significant correlation with poor prognosis in the lung cancer. Furthermore, the MYC inhibitor demonstrated more sensitivity for the major nodules than minor nodules.

This study validated molecular distinctions between samples from major and minor nodules in patients with sMPLC at both genomic and transcriptomic levels. The major nodules exhibited heightened activity in tumor cell proliferation pathways and demonstrated malignancy-related biological characteristics, which correlated with pathological assessment results.

The treatment of metastasized gastroesophageal adenocarcinoma largely depends on molecular profiling based on immunohistochemical procedures. Therefore, the examination of HER2, PD-L1, and dMMR/MSI is recommended by the majority of clinical practice guidelines, as positive expression leads to different treatment approaches. Data from large phase-III trials and consequent approvals in various countries enable physicians to offer their patients several therapy options including immunotherapy, targeted therapy, or both combined with chemotherapy. The introduction of novel therapeutic targets such as CLDN18.2 leads to a more complex decision-making process as a significant number of patients show positive results for the co-expression of other biomarkers besides CLDN18.2. The aim of this review is to summarize the current biomarker landscape of patients with metastatic gastroesophageal tumors, its direct clinical impact on daily decision-making, and to evaluate current findings on biomarker co-expression. Furthermore, possible treatment strategies with multiple biomarker expression are discussed.

Numerous studies have consistently indicated a connection between the clinical results of individuals who receive immunotherapy and their nutritional condition. This study aims to evaluate the predictive capacity of the Nutritional Risk Index (NRI) in gastric cancer patients who are undergoing treatment with immune checkpoint inhibitors (ICIs). This study included a total of 146 individuals diagnosed with gastric cancer and received a combination of chemotherapy and immunotherapy using PD-1/PD-L1 inhibitors. The threshold was established by utilizing the receiver operating characteristic (ROC) curve. To analyze the clinical and pathological characteristics of the 2 groups, we performed Chi-square test or Fisher exact test. Univariate and multivariate analyses were performed to assess the factors influencing progression-free survival (PFS) and overall survival (OS) rates. Additionally, we developed nomograms to accurately predict the probability of 1- year and 3-year survival in these patients. According to the threshold, there were 38 (26.0%) patients in the low NRI category and 108 (74.0%) patients in the high NRI category. In the high NRI group, the median survival PFS was 32.50 months, while it was 11.77 months in the low NRI group. Likewise, the average survival OS in the 2 categories was 18.57 months compared to an indefinite duration. Individuals classified in the low NRI category encountered reduced PFS and OS, with a hazard ratio (HR) of 2.015 and 2.093 respectively, along with corresponding P-values of .009 and .006. The analysis of multiple variables showed that the number of platelets and TNM stage were separate factors that predicted both PFS and OS. Additionally, NRI was further recognized as a separate predictive factor for overall survival. The analysis of a specific subgroup revealed that individuals in the low NRI category experienced worse PFS and OS, especially within the group receiving ICIs. The C-index and the respective 95% CI of the nomograms to forecast the likelihood of PFS and OS survival were 0.646 (0.583-0.709) and 0.693 (0.635-0.751). NRI has the capability to forecast the clinical results of individuals who were diagnosed with gastric cancer and have received ICIs. This makes it a feasible biomarker for identifying patients who could benefit from ICIs.

Digestive system neoplasms are highly heterogeneous and exhibit complex resistance mechanisms that render anti-programmed cell death protein (PD) therapies poorly effective. The tumor microenvironment (TME) plays a pivotal role in tumor development, apart from supplying energy for tumor proliferation and impeding the body's anti-tumor immune response, the TME actively facilitates tumor progression and immune escape via diverse pathways, which include the modulation of heritable gene expression alterations and the intricate interplay with the gut microbiota. In this review, we aim to elucidate the mechanisms underlying drug resistance in digestive tumors, focusing on immune-mediated resistance, microbial crosstalk, metabolism, and epigenetics. We will highlight the unique characteristics of each digestive tumor and emphasize the significance of the tumor immune microenvironment (TIME). Furthermore, we will discuss the current therapeutic strategies that hold promise for combination with cancer immune normalization therapies. This review aims to provide a thorough understanding of the resistance mechanisms in digestive tumors and offer insights into potential therapeutic interventions.

Combining chemotherapy with immune checkpoint inhibitors (ICIs) that target the programmed death-1 (PD-1) protein has been shown to be a clinically effective first-line treatment for human epidermal growth factor receptor 2 (HER2)-negative and -positive advanced or metastatic gastric cancer (GC). Currently, PD-1 inhibitors combined with chemotherapy are the standard treatment for patients with HER2-negative/positive locally advanced or metastatic GC. Programmed death-ligand 1 (PD-L1) expression, as assessed using immunohistochemistry (IHC), is a crucial biomarker for predicting response to anti-PD-1/PD-L1 agents in various solid tumors, including GC. In GC, the PD-L1 IHC test serves as a companion or complementary diagnostic test for immunotherapy, and an accurate interpretation of PD-L1 status is essential for selecting patients who may benefit from immunotherapy. However, PD-L1 IHC testing presents several challenges that limit its reliability as a biomarker for immunotherapy. In this review, we provide an overview of the current practices of immunotherapy and PD-L1 testing in GC. In addition, we discuss the clinical challenges associated with PD-L1 testing and its future use as a biomarker for immunotherapy. Finally, we present prospective biomarkers currently under investigation as alternative predictors of immunotherapy response in GC.

Immunology-based therapies are emerging as an effective cancer treatment, using the body's immune system to target tumors. Immune checkpoints, which regulate immune responses to prevent tissue damage and autoimmunity, are often exploited by cancer cells to avoid destruction. The discovery of checkpoint proteins like PD-1/PD-L1 and CTLA-4 was pivotal in developing cancer immunotherapy. Immune checkpoint inhibitors (ICIs) have shown great success, with FDA-approved drugs like PD-1 inhibitors (Nivolumab, Pembrolizumab, Cemiplimab), PD-L1 inhibitors (Atezolizumab, Durvalumab, Avelumab), and CTLA-4 inhibitors (Ipilimumab, Tremelimumab), alongside LAG-3 inhibitor Relatlimab. Research continues on new checkpoints like TIM-3, VISTA, B7-H3, BTLA, and TIGIT. Biomarkers like PDL-1 expression, tumor mutation burden, interferon-γ presence, microbiome composition, and extracellular matrix characteristics play a crucial role in predicting responses to immunotherapy with checkpoint inhibitors. Despite their effectiveness, not all patients experience the same level of benefit, and organ-specific immune-related adverse events (irAEs) such as rash or itching, colitis, diarrhea, hyperthyroidism, and hypothyroidism may occur. Given the rapid advancements in this field and the variability in patient outcomes, there is an urgent need for a comprehensive review that consolidates the latest findings on immune checkpoint inhibitors, covering their clinical status, biomarkers, resistance mechanisms, strategies to overcome resistance, and associated adverse effects. This review aims to fill this gap by providing an analysis of the current clinical status of ICIs, emerging biomarkers, mechanisms of resistance, strategies to enhance therapeutic efficacy, and assessment of adverse effects. This review is crucial to furthering our understanding of ICIs and optimizing their application in cancer therapy.

Tumor mutation burden (TMB) has been considered a biomarker for utilization of immune checkpoint inhibitors(ICIs), but whole exome sequencing(WES) and cancer gene panel(CGP) based on next generation sequencing for TMB detection are costly. Here, we use transcriptome data of TCGA to construct a model for TMB prediction in gastrointestinal tumors.

Transcriptome data, somatic mutation data and clinical data of four gastrointestinal tumors from TCGA, including esophageal cancer (ESCA), stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ). Using R, we performed visual analysis of somatic mutation data, differentially expressed genes (DEGs) function enrichment analysis, gene set enrichment analysis (GSEA), and estimated TMB value in clinic. Finally, a deep neural network (DNN) model was constructed for TMB prediction.

Visualization of somatic mutation data summarized the classification of mutation, frequency of each mutation type, and top-mutated genes. GSEA showed the enrichment of CD4+/CD8+ T cells in the high TMB group and the activation of tumor suppressing pathways. Single-sample GSEA (ssGSEA) manifested that the high-TMB group had higher level of multiple immune cells infiltration. In addition, distribution of TMB was related to clinical parameters. Like age, M stage, N stage, AJCC stage, and overall survival(OS). After model optimization using genetic algorithm, in the training set, validation set, and testing set, the Pearson relevance coefficient r between predicted values and actual values reaches 0.98, 0.82, and 0.92, respectively; the coefficient of determination R2 is 0.95, 0.82, and 0.7, respectively.

TMB correlates with clinicopathological parameters in gastrointestinal carcinoma, and patients with high TMB have higher levels of immune infiltration. In addition, the DNN model based on 31 genes predicts TMB of gastrointestinal tumors in a high accuracy.

Recent studies have revealed that inflammatory factors and nutritional status of patients with advanced gastric cancer (AGC) are related to the efficacy of drug therapy and patient prognosis. This study seeks to evaluate the correlation between inflammatory markers, nutritional status, and clinical outcomes of immune checkpoint inhibitor (ICI)-based therapies among inoperable AGC patients.

This retrospective study included 88 AGC patients who received ICIs combined with chemotherapy. Inflammatory and nutritional indicators from patients before and after two cycles of treatment were collected. Finally, the correlations between these indicators and the clinical response and survival of AGC patients with ICI treatment were examined.

The results revealed that an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0, neutrophil count to lymphocyte count ratio (NLR) < 2.84, platelet count to lymphocyte count ratio (PLR) < 82.23, lymphocyte count to monocyte count ratio ≥ 2.35, the hemoglobin, albumin, lymphocyte and platelet score (HALP) ≥ 31.17, prognostic nutritional index (PNI) ≥ 46.53, albumin ≥ 41.65, the decreased HALP group and the decreased PNI group were significantly correlated with improved objective response rate. Additionally, an ECOG PS score of 0, NLR < 2.84 and the decreased HALP group was associated with a superior disease control rate. Meanwhile, an ECOG PS score of 0 (progression-free survival (PFS): P = 0.003; overall survival (OS): P = 0.001) and decreased PLR following treatment (PFS: P = 0.011; OS: P = 0.008) were significant independent predictors of PFS and OS. Lastly, a systemic immune inflammation index ≥ 814.8 was also a positive independent predictor of OS among AGC patients.

Our study supports the potential of inflammatory and nutritional factors to serve as predictors of the efficacy and prognosis in patients undergoing ICI-based therapies for AGC. However, further investigations are necessary to validate these findings.

The emergence of robotic surgical systems compensated for the technological shortcomings of laparoscopic approaches. However, whether robotic gastrectomy (RG) has better perioperative outcomes and survival than laparoscopic gastrectomy (LG) for gastric cancer (GC) is still unclear but increasingly drawing attention.

In this systematic review and meta-analysis, we searched PubMed, EMBASE, Web of Science, and Cochrane Library as of 20 January 2024, and referenced a list of eligible articles for all published studies comparing RG and LG for patients with GC. Data on study characteristics, individual characteristics, and outcome parameters were extracted. The quality of studies was assessed using the Revised Cochrane risk-of-bias 2 tool and the risk of bias in nonrandomized studies of interventions tool. The main outcome measures were overall survival (OS) and disease-free survival (DFS).

The authors identified 3641 articles, of which 72 studies (30 081 patients) were included in the meta-analysis. Compared with LG, RG was associated with higher OS [hazard ratio (HR)=0.89, 95% CI=0.83-0.96], lower rate of overall postoperative complications [odds ratio (OR)=0.77, 95% CI=0.71-0.84], longer operating time [mean difference (MD)=35.53, 95% CI=29.23-41.83], less estimated blood loss (MD=-37.45, 95% CI=-46.24 to -28.67), a higher number of retrieved lymph nodes (MD=1.88, 95% CI=0.77-3.00), faster postoperative recovery, and lower rate of conversion (OR=0.44, 95% CI=0.36-0.55). Mortality and DFS were not significantly different between the two groups. The subgroup of meta-analysis results also showed the advantages of robotic surgery over laparoscopic surgery in intracorporeal reconstruction, total gastrectomy, Ⅰ/Ⅱ stage, and BMI≥25, especially for patients with stage Ⅰ/Ⅱ, there are better OS and DFS.

Our findings point to robotic surgery having great benefits compared with laparoscopic surgery in GC. Our study may help inform decision-making in applying robotic surgical systems to clinical treatment.

Gastric cancer (GC) poses a significant health challenge worldwide, necessitating the identification of predictive biomarkers to improve prognosis. Dysregulated lipid metabolism is a well-recognized hallmark of tumorigenesis, prompting investigation into apolipoproteins (APOs). In this study, we focused on apolipoprotein D (APOD) following comprehensive analyses of APOs in pan-cancer. Utilizing data from the TCGA-STAD and GSE62254 cohorts, we elucidated associations between APOD expression and multiple facets of GC, including prognosis, tumor microenvironment (TME), cancer biomarkers, mutations, and immunotherapy response, and identified potential anti-GC drugs. Single-cell analyses and immunohistochemical staining confirmed APOD expression in fibroblasts within the GC microenvironment. Additionally, we independently validated the prognostic significance of APOD in the ZN-GC cohort. Our comprehensive analyses revealed that high APOD expression in GC patients was notably associated with unfavorable clinical outcomes, reduced microsatellite instability and tumor mutation burden, alterations in the TME, and diminished response to immunotherapy. These findings provide valuable insights into the potential prognostic and therapeutic implications of APOD in GC.

Laryngeal squamous cell carcinoma (LSCC) is a common cancer with high mortality and tumor mutation burden (TMB), and high TMB is associated with favorable survival. The expression, mutation, and survival data were obtained from The Cancer Genome Atlas database. The mutation and differentially expressed genes were analyzed using limma R package. The function enrichment was analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. TMB-related genes were identified by Weighted correlation network analysis. Univariate, multivariate and Lasso cox analyses were used to determine hub genes. The risk model and mRNA expression was validated by Receiver Operating Characteristic curve and qRTPCR. The immune infiltration was analyzed by xCELL. The drug sensitivity was determined through gene set cancer analysis database. We identified 1129 differentially expressed genes related to TMB. Enrichment analysis showed they were associated with immune response. ANKLE1 and PPP1R14A were screened out as hub genes. Receiver Operating Characteristic curve identified that the risk model had an effective prognosis value in progression-free interval of LSCC. Immune infiltration levels of 16 immune cells were significantly changed in high risk score group compared with low risk score group. ANKLE1 and PPP1R14A expressions were significantly upregulated in tumor group, which was consistent with qRTPCR results, and associated with better prognosis. ANKLE1 was negatively related to many drug sensitivities, while PPP1R14A was positively related to some drug sensitivities. We constructed an effective risk model constructed by ANKLE1 and PPP1R14A which was related to TMB in LSCC.

Immune checkpoint inhibitors (ICIs) have shown encouraging treatment efficacy for upper gastrointestinal cancers (UGICs). However, durable clinical responses only existed in a minority of patients. We evaluated evidence predicting survival benefits to identify the optimal population followed by ICI-based therapy.

A comprehensive search was performed using PubMed, Embase, Cochrane Library, and Web of Science to identify clinical trials for UGICs with ICI-based therapy. The outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation System (GRADE).

Thirty-six studies comprising 12,440 patients were included for quantitative synthesis. Patients with PD-L1-positive (OR = 2.08, p < 0.00001), EBV+ (OR = 8.47, p = 0.003) tumors were more likely to respond to ICI treatment. Moreover, OS was significantly improved with the statistical subgroup difference concerning sex (p = 0.02) and region (p = 0.02). An exploratory subgroup analysis showed significantly improved OS with ICI plus chemotherapy in patients with CPS ≥ 10 (HR = 0.66, p = 0.001) and CPS ≥ 1 (HR = 0.75, p < 0.00001).

UGIC patients with PD-L1-positive, EBV + status are associated with a better therapeutic response to ICI-based therapy. The male patients and Asian patients could derive more survival benefits following ICI treatment than female and non-Asian ones. A combination of prognostic and predictive factors was suggested to help guide immunotherapy decision-making in UGIC patients.

RNA modifications represent a novel category of biological molecule alterations, characterized by three primary classes of proteins: writers, erasers, and readers. Numerous studies indicate that the dysregulation of these RNA modifications is linked to cancer development and may offer new therapeutic avenues for treatment. In our research, we focused on eight specific genes associated with RNA modifications (RMRGs) to comprehensively analyze their distinct functions in gastric cancer (GC). Furthermore, we aimed to elucidate the roles of RMRGs concerning clinicopathological characteristics, tumor microenvironment, and patient prognosis.

In this study, we examined the expression and mutations of RMRGs in gastric cancer (GC) using data from TCGA-STAD (The Cancer Genome Atlas; Stomach adenocarcinoma) and the gene expression omnibus (GSE66229). We identified two subtypes of RMRGs and three gene clusters through consensus clustering analysis, assessing their differences in prognosis and immune cell infiltration patterns. Subsequently, we developed an RMRGs score to evaluate GC prognosis and highlight general immune features within the tumor microenvironment (TME). Lastly, we focused on MAMDC2 to validate its expression in GC and explore the effects of a MAMDC2 inhibitor on GC tumor cells.

We discovered 94 differentially expressed RMRGs common to both the TCGA-STAD and GEO datasets. Notable differences in prognosis and immune cell infiltration were observed between the two RMRGs subtypes and three gene clusters. The RMRGs score emerged as an independent prognostic factor related to the tumor microenvironment (TME) characteristics in gastric cancer (GC). Reducing MAMDC2 levels enhanced cell migration and invasion while decreasing proliferation in vitro.

In conclusion, this study comprehensively analyzed the role of RMRGs on GC. Our study firstly proposed RMRGs score and demonstrated its potential to be biomarkers for prognosis and immune characteristics. Consequently, RMRGs score is of great clinical significance and can be utilized to develop individualized.

Gastric cancer (GC) is a common malignancy that presents challenges in patient care worldwide. The mismatch repair (MMR) system is a highly conserved DNA repair mechanism that protects genome integrity during replication. Deficient MMR (dMMR) results in an increased accumulation of genetic errors in microsatellite sequences, leading to the development of a microsatellite instability-high (MSI-H) phenotype. Most MSI-H/dMMR GCs arise sporadically, mainly due to MutL homolog 1 (MLH1) epigenetic silencing. Unlike microsatellite-stable (MSS)/proficient MMR (pMMR) GCs, MSI-H/dMMR GCs are relatively rare and represent a distinct subtype with genomic instability, a high somatic mutational burden, favorable immunogenicity, different responses to treatment, and prognosis. dMMR/MSI-H status is a robust predictive biomarker for treatment with immune checkpoint inhibitors (ICIs) due to high neoantigen load, prominent tumor-infiltrating lymphocytes, and programmed cell death ligand 1 (PD-L1) overexpression. However, a subset of MSI-H/dMMR GC patients does not benefit from immunotherapy, highlighting the need for further research into predictive biomarkers and resistance mechanisms. This review provides a comprehensive overview of the clinical, molecular, immunogenic, and therapeutic aspects of MSI-H/dMMR GC, with a focus on the impact of ICIs in immunotherapy and their potential as neoadjuvant therapies. Understanding the complexity and diversity of the molecular and immunological profiles of MSI-H/dMMR GC will drive the development of more effective therapeutic strategies and molecular targets for future precision medicine.

The incidence and mortality rates of gastric cancer (GC) remain alarmingly high worldwide, imposing a substantial healthcare burden. In this study, we utilized data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A 4-gene prognostic model was developed to predict patient prognosis, and its accuracy was validated across multiple datasets. Patients with a low-risk score exhibited improved prognosis, elevated tumor mutation burden, heightened sensitivity to both immunotherapy and conventional chemotherapy. Notably, our investigation revealed that the key gene RGS5 positively modulates the expression of mismatch repair proteins via c-Myc. Furthermore, co-immunoprecipitation (COIP) assays demonstrated the interaction between RGS5 and c-Myc. Additionally, we confirmed that RGS5 regulates c-Myc through the ubiquitin-proteasome pathway. Moreover, RGS5 was identified as a positive regulator of PD-L1 expression and exhibited a negative correlation with the majority of immune cells. These findings underscore the potential of RGS5 as a novel biomarker and therapeutic target in the context of GC.