This review synthesizes evidence on NUF2 in digestive system cancers, delineates its oncogenic mechanisms, and evaluates its potential as a diagnostic and therapeutic target, addressing unmet needs for these high-incidence, poor-prognosis malignancies. NUF2, a key cell cycle protein, is significantly overexpressed in digestive system cancers. Mechanistic studies reveal that it promotes tumorigenesis by driving genomic instability, inhibiting apoptosis, inducing epithelial–mesenchymal transition, and remodeling the tumor immune microenvironment. Emerging therapeutic strategies–including natural compounds (e.g., berberine, fisetin) and peptide-based vaccines–shows preclinical efficacy in targeting NUF2. NUF2 represents a promising biomarker and therapeutic target for digestive system cancers. While preclinical evidence is compelling, clinical translation remains at an early stage. Future efforts should focus on large-scale clinical validation, optimizing targeted interventions, and developing combinatorial approaches to improve patient outcomes.

Boron Neutron Capture Therapy (BNCT) is a binary cancer therapy that involves boron (10B) drug administration and epithermal/thermal neutron irradiation. The nuclear fission reaction between low-energy thermal neutrons and 10B atoms accumulated in cancer cells generate high linear energy transfer (LET) species (α and 7Li particles). These species are short range (4-10 μm, less than a cell diameter) and therefore offer potential to kill cancer cells selectively and spare surrounding healthy cells if the 10B drug can be targeted specifically and sufficiently to cancer cells. Numerous studies have explored the role of selected targets on the influence of 10B transport to make progress in developing novel, safe and effective 10B carriers. These findings would expand the clinical BNCT services to more patients, with potential to make BNCT a more precise and effective treatment modality for various types of cancer. This review summarizes the current knowledge of a variety of potential targets for 10B transport in BNCT.

Chimeric antigen receptor T-cell (CAR-T) therapy has achieved remarkable outcomes in the treatment of hematological malignancies, yet its efficacy is severely compromised in digestive system tumors. The inherent physical barriers and immunosuppressive tumor microenvironment (TME) of digestive tumors hinder the infiltration and effector function of antitumor immune cells, greatly limiting the efficacy of conventional immunotherapies and creating an urgent demand for novel targeted immunotherapeutic strategies. As pivotal resident immune cells in the TME, macrophages possess powerful phagocytic activity and antigen-presenting ability, making them ideal candidates for tumor immunotherapy. Chimeric antigen receptor macrophages (CAR-Ms) can penetrate and remodel the immunosuppressive TME and directly eliminate tumor cells, exhibiting unique advantages and great application potential for the treatment of digestive system tumors. Herein, we provide a comprehensive narrative review of the latest research advances in CAR-M therapy for digestive system tumors. This review mainly focuses on the cellular origins, innovative engineering and genetic modification strategies, and underlying antitumor mechanisms of CAR-Ms, as well as systematically discusses the current challenges and future prospects of CAR-M-based digestive tumor therapy. We aim to provide valuable theoretical references for the development and clinical translation of novel immunotherapies for digestive system tumors. With the rapid development of precision immunomedicine, CAR-M therapy is expected to become a promising alternative therapeutic strategy for clinical digestive system tumors treatment.

Pancreatic cancer is one of the most aggressive malignant tumors with the poorest prognosis worldwide. In recent years, environmental factors have played a very important role in the occurrence and development of pancreatic cancer. Among these, environmental factors such as obesity, smoking, alcohol consumption, altitude, dietary patterns, and chemical exposure can affect physiological function of the pancreas by inducing epigenetic changes or promote the development of pancreatic cancer through mechanisms such as chronic inflammation. Avoiding these environmental risk factors through public health interventions and individual behavioral changes is expected to significantly reduce the incidence of pancreatic cancer and improve patient prognosis. Therefore, from the perspective of environmental factors, this article systematically reviews the risk factors related to pancreatic cancer and the corresponding prevention and treatment measures, thereby providing a theoretical basis for the prevention and early screening of pancreatic cancer.

Boron neutron capture therapy (BNCT), a precision radiotherapy modality, has shown significant promise in targeted cancer treatment. Like conventional radiotherapy, the development of radioresistance hinders the efficacy of BNCT. Nevertheless, the physical parameters in BNCT induce the massive anti-tumor response compared to low-LET radiotherapy. Recent advancements have highlighted its synergistic potential with immunotherapy. In this review, we explore how the unique physical-to-biological trajectory of BNCT drives a potent “Cold-to-Hot” transformation of the tumor microenvironment. We describe how radiotherapy remodels the tumor microenvironment and extrapolate the potential mechanism by which BNCT influences anti-tumor response based on the principles of conventional radiotherapy. BNCT-induced immunogenic cell death and neoantigen presentation activate dendritic cells and CD8⁺ T-cells. Besides its immunostimulatory effects, BNCT may also exhibit immunosuppressive effects. Both the recruitment of immunosuppressive cells and tumor hypoxia can influence BNCT efficacy, and studies have shown that targeting these factors can enhance BNCT outcomes. Looking forward, we propose that combining BNCT with CAR-T cell therapy or immune checkpoint inhibitors represents one of the most promising directions for its future application. We hope this review provides novel insights into the clinical translation of BNCT.

Background and Objective:Gastric cancer (GC) constitutes a significant global health issue, with its incidence and mortality rates ranking fifth worldwide. In recent years, atmospheric pollutants, as one of the environmental factors, have increasingly been recognized as critical risk factors in the development of GC. Epidemiological studies indicate that atmospheric pollutants such as particulate matter, gaseous pollutants, polycyclic aromatic hydrocarbons, and persistent organic substances are associated with the onset and progression of GC. Currently, the pathogenic mechanisms by which atmospheric pollutants contribute to GC remain incompletely elucidated. These mechanisms may involve pathways such as inflammatory responses, oxidative stress, immunomodulation, metabolism, gut microbiota interactions, and genetic cross-talk, all of which promote the development and progression of GC. Additionally, this article summarizes the current limitations of research and outlines future research directions, aiming to provide a reference for future studies. Methods:This study conducted a literature review by searching the PubMed and Web of Science databases to identify the latest research findings regarding the mechanisms by which atmospheric pollutants promote the occurrence and development of GC. Based on these findings, a narrative review was generated. Key Content and Findings:This article introduces the classification of major atmospheric pollutants and epidemiological studies on their association with GC. It summarizes the mechanisms by which atmospheric pollutants promote the occurrence and development of GC. In addition, it also summarizes the limitations of current research and future research directions. These advances will help provide more theoretical basis for the role of atmospheric pollutants in promoting the development of GC. Conclusions:Atmospheric pollutants can promote the occurrence and development of GC through pathways such as inflammatory response, oxidative stress, immune regulation, metabolism, intestinal microecology, and genetic interaction. In the future, more extensive epidemiological studies and more in-depth mechanism research are needed to further explore the mechanisms by which atmospheric pollutants contribute to GC. Meanwhile, this will also be beneficial to the formulation of relevant public health policies.

BackgroundColorectal cancer poses a major health challenge in Gansu Province, being one of the top causes of both incidence and mortality among gastrointestinal cancers. This study aims to analyze the epidemiological patterns of colorectal cancer in Gansu Province, while exploring potential associations with environmental determinants.MethodWe analyzed clinical records of all colorectal cancer cases from 2013 to 2023, retrieved from hospital information systems across 87 counties in Gansu Province, encompassing municipal, district, county, and township-level medical institutions. A thorough analysis was conducted employing various methods, including Joinpoint regression, spatial autocorrelation, spatiotemporal scanning, and Geo-detector analysis, using specialized software (Joinpoint 5.0, ArcGIS 10.8, and SaTScan). Our study explored the relationship between colorectal cancer incidence in Gansu Province and 14 Environmental factors.ResultThe results indicate a steady rise in colorectal cancer incidence over the 11-year period and the highest age-standardized incidence rates of colorectal cancer occurred in Jinchuan, Chengguan, Suzhou, Baiyin, and Liangzhou districts, contrasting sharply with the significantly lower rates documented in Liangdang, Kang, Heshui, Huining, Zhengning, and Cheng counties. Spatial and spatiotemporal analyses identified several significant high- and low-risk clusters of colorectal cancer throughout Gansu Province, demonstrating both spatial and temporal variability in disease distribution. The Geo-detector indicated that colorectal cancer incidence was significantly linked to the distribution of climatic conditions (precipitation and temperature), ecological factor, and certain air pollutants. Multivariate spatial analysis was used to further explore the relationship between environmental factors and the incidence of colorectal cancer.ConclusionOur research highlighted notable spatial variability in colorectal cancer incidence across Gansu Province, with geospatial and spatiotemporal analyses uncovering high-risk clusters and important environmental factors.

BACKGROUND:The tight junction protein claudin18.2 (CLDN18.2) has been implicated in poor prognosis and suboptimal immunotherapy response in gastric cancer (GC). This study investigates the clinicopathological relevance of CLDN18.2 expression and its association with molecular subtypes in GC patients from a high-incidence region, combining transcriptomic and proteomic approaches to explore how CLDN18.2 contributes to progression and metastasis. METHODS:A retrospective cohort of 494 GC patients (2019-2024) underwent immunohistochemical analysis for CLDN18.2, Epstein-Barr virus (Epstein-Barr virus-encoded RNA), p53, human epidermal growth factor receptor 2 (HER2), and mismatch repair proteins (MLH1, MSH2, PMS2, and MSH6). CLDN18.2 positivity was defined as moderate to strong (2+/3+) membranous staining in ≥75% of tumor cells. Clinicopathological correlations, biomarker associations, and survival outcomes were evaluated. Transcriptomic and proteomic sequencing was performed to explore molecular mechanisms. RESULTS:CLDN18.2 positivity was observed in 26.9% (133/494) of gastric adenocarcinomas. CLDN18.2-positive tumors correlated with TNM stage (p = .003) and shorter overall survival (p = .018). No associations were identified with age, sex, HER2 status, microsatellite instability, or Epstein-Barr virus infection. Transcriptomic profiling revealed CLDN18.2-high tumors enriched in pathways involving cell junction disruption, signaling regulation, and immune modulation. Proteomic profiling showed that tumors with high CLDN18.2 were enriched in multiple mechanism-related pathways such as integrated metabolic reprogramming, cytoskeletal recombination, immune microenvironment dysregulation, and pro-survival signaling. These mechanisms may collectively contribute to tumor progression and metastasis. CONCLUSIONS:CLDN18.2 overexpression is associated with poor prognosis in GC patients. Transcriptomic and proteomic analyses demonstrate that CLDN18.2 promotes tumor progression and metastasis, underscoring its potential as an independent prognostic factor in regions with a high incidence of GC.

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide, underscoring the need for effective immunotherapeutic strategies. Here, we generated monoclonal antibodies against zona pellucida glycoprotein 3 (ZP3), developed ZP3-targeting chimeric antigen receptor macrophages (CAR-M), and evaluated their therapeutic potential in HCC. The recombinant extracellular domain of human ZP3 was expressed in HEK293F cells and used to immunize mice. CD138⁺ plasma cells were enriched and subjected to antigen-specific single-cell screening. Paired immunoglobulin variable-region sequences were recovered by nested polymerase chain reaction, followed by antibody cloning, expression, and purification. An anti-ZP3 single-chain variable fragment was incorporated into a lentiviral CAR construct and expressed in THP-1 cells, which were subsequently differentiated into macrophage-like cells. The phagocytic activity, cytotoxicity, polarization phenotype, cytokine secretion, in vivo antitumor efficacy, biodistribution, and preliminary safety of ZP3-targeting CAR-M were evaluated in HCC cell-based assays and Huh7 xenograft models. Highly purified anti-ZP3 monoclonal antibodies were generated and shown to recognize membrane-associated ZP3 on Huh7 cells. Anti-ZP3 antibody treatment significantly suppressed tumor growth in peripheral blood mononuclear cell-reconstituted NOD-Scid mice. ZP3-targeting CAR-M exhibited efficient CAR expression and specific ZP3 binding, together with enhanced phagocytosis and cytotoxicity against HCC cells compared with control macrophages. Antigen engagement promoted an M1-like phenotype, characterized by increased CD80 and CD86 expression, reduced CD163 and CD206 expression, and enhanced secretion of IL-6, IL-1β, TNF-α, and IFN-γ. In Huh7 xenograft-bearing mice, systemic administration of CAR-M significantly delayed tumor progression. After treatment, body weight remained stable, most serum biochemical parameters responded basically normal, and major organs exhibited favorable tolerability. ZP3 is a promising immunotherapeutic target in HCC. ZP3-directed antibodies and CAR-M demonstrated preclinical antitumor activity, supporting further development of ZP3-targeted immunotherapies.

BACKGROUND: Zona pellucida glycoprotein 3 (ZP3) is an important member of the zona pellucida glycoprotein family. However, the underlying mechanisms and immune regulation in hepatocellular carcinoma (HCC) remain unclear. METHODS: The protein expression level of ZP3 in HCC tissues was detected via Western blotting (WB) and immunohistochemistry (IHC). The impact of ZP3 on tumor microenvironment (TME) modulation in HCC was analyzed via the TCGA database, and its potential for immunotherapy response was assessed via the Tumor Immune Dysfunction and Exclusion (TIDE) database. Lentivirus-mediated knockdown and overexpression of ZP3 were performed in HCC cell lines, both in vitro and in vivo via various techniques, including immunofluorescence (IF), EdU, wound healing, colony formation, migration, transcriptome sequencing, flow cytometry, and xenograft assays. RESULTS: We confirmed that ZP3 protein levels were significantly greater in HCC tissues than in normal tissues through WB and IHC analyses. Functionally, ZP3 knockdown in Huh7 cells reduced proliferation, migration, and invasion and slowed tumor growth in xenograft models; conversely, ZP3 overexpression in LM3 cells intensified these oncogenic traits. Mechanistically, enrichment analysis of the transcriptome data suggested that ZP3 might promote HCC progression via the Notch signaling pathway. Furthermore, ZP3 knockdown decreased key components of the Notch pathway (Jagged1, Notch1, NICD1, and Hes1), whereas ZP3 overexpression activated this pathway. ZP3 expression was significantly correlated with tumor-infiltrating immune cells (such as M0 macrophages, T cells, and NK cells) and TME scores in HCC. Notably, patients with high ZP3 levels presented lower TIDE scores, indicating reduced immune evasion potential and a better response to immunotherapy. CONCLUSION: ZP3 promotes HCC progression by activating the Notch pathway and modulating the TME, highlighting its potential as both a prognostic biomarker and a therapeutic target.

Glioblastoma (GBM) is the most prevalent type of malignant primary brain tumor. Preclinical research serves a key role in investigating the development and mechanism of GBM tumor. However, the dynamic and non‑invasive evaluation of tumors in animals faces challenges, such as the limited sensitivity of clinical instruments and insufficient spatial resolution for mouse brain tumors. The present study aimed to establish an in vivo mouse GBM model and evaluate the model using high resolution small animal positron emission tomography‑computed tomography (PET‑CT) and magnetic resonance imaging (MRI). Metabolism was compared between the normal brain and tumor tissue by using 1H‑magnetic resonance spectroscopy (1H‑MRS). T2‑weighted imaging (T2WI) MRI detected the tumor in the brain 7 days after injection of GL261 cells, with tumor sizes of 1.263, 4.917 and 13.85 mm3 on days 7, 14 and 21, respectively. 1H‑MRS demonstrated that the levels of tissue metabolites such as lactate and total choline increased, while those representing neurological function of the brain such as total N‑acetylaspartate decreased in tumor compared with the normal brain tissues. PET‑CT imaging confirmed the tumor detected by MRI. At 6‑120 min post 18F‑fluorodeoxyglucose (FDG) administration, the standard uptake value (SUV) in tumor tissue gradually increased, while the SUV value in normal brain tissue gradually decreased. SUV in the liver and kidneys decreased, while SUV in the bladder increased in a time‑dependent manner. Pharmacokinetic analysis showed that the distribution of FDG in brain and tumor tissue conformed to a two‑tissue compartment model. This model consists of a plasma compartment and two tissue compartments representing free FDG and phosphorylated FDG within brain or tumor tissue. The model parameters are defined as follows: Fractional blood volume (vB)=3.6%, k1 (forward transport rate)=1.844, k2 (reverse transport rate)=3.844 and k3 (phosphorylation rate)=0.280 in brain and vB=2.3%, k1=0.797, k2=2.722 and k3=0.319 in tumor tissue, respectively. The tumors observed by MRI and PET‑CT imaging were ultimately confirmed through morphological and pathological analysis. Compared with normal brain tissue, glioma tissue exhibited significantly elevated glucose transporter type 1 protein levels. In conclusion, the model was confirmed by high‑resolution small animal PET‑CT and MRI, as well as morphological and pathological approaches.

Hepatocellular carcinoma (HCC) is a major public health challenge in China, with regional disparities often linked to environmental factors. Gansu Province, characterized by complex topography and climatic heterogeneity, provides a unique setting to examine these determinants. This study characterized the spatiotemporal patterns of HCC incidence in Gansu (2013–2023) and quantified the contributions of terrain, climate, and air quality. This population-based ecological study analyzed county-level HCC incidence data (2013–2023) from the Gansu Provincial Cancer Registry. Age-standardized incidence rates (ASIRs) and temporal trends were assessed via direct standardization and Joinpoint regression. Spatial heterogeneity and risk regions (high/low) were identified using a Bayesian hierarchical Besag–York–Mollié (BYM) model. To evaluate environmental drivers, long-term exposures (2003–2013) were correlated with ASIR using Spearman’s rank analysis. Multicollinearity was assessed via Variance Inflation Factor (VIF). Finally, the independent attribution of environmental factors was quantified using Ridge Regression with cross-validated penalization, with coefficient stability validated through 1,000 bootstrap resamples. The HCC ASIR in Gansu peaked in 2017 (16.30 per 100,000) before declining to 7.55 by 2023, with a consistent male predominance (sex ratio 2.42:1). Bayesian analysis revealed significant spatial clustering, with high-risk regions concentrated in central and southern counties (e.g., Gannan Plateau). Quantitative attribution demonstrated that topographic features were the dominant drivers, collectively explaining 73.5

Background: The incidence of young-onset gastric cancer (GC) has been increasing in recent years. With high heterogeneity and non-specific early symptoms, it is often diagnosed late, posing a serious threat to young populations. This study aimed to identify diagnostic biomarkers for young-onset GC through low-cost routine laboratory tests and explore their interactions and combined effects. Methods: Data from young-onset GC patients (≤45 years, n = 709) and gastric precancerous lesions (GPL) patients (n = 3,355) diagnosed at the Second Hospital of Lanzhou University between January 2012 and December 2023 were analyzed. Logistic regression and classification and regression tree (CART) models evaluated 66 clinical and laboratory variables to predict young-onset GC. Results: High-order interaction analysis using the CART revealed that among young GPL patients (≤45 years) with platelet distribution width (PDW) ≤14.050 fl, platelet-to-lymphocyte ratio (PLR) >164.464, albumin (ALB) ≤42.850 g/L, and low-density lipoprotein (LDL) > 2.175 mmol/L, the GC incidence was 69.9%. In young male GPL patients (≤45 years), GC incidence increased to 74.0% when aspartate aminotransferase/alanine aminotransferase (AST/ALT) > 0.905, PLR > 94.378, Urea > 4.650 mmol/L, ALB ≤40.05 g/L, and total cholesterol (TC) > 3.055 mmol/L. PDW, low-density lipoprotein/high-density lipoprotein (LDL/HDL), and alkaline phosphatase (ALP) were identified as potential biomarkers for young-onset GC in females. Conclusions: This study identified novel biomarkers associated with young-onset GC, providing substantial evidence for the early detection and diagnosis of high-risk populations with the potential to improve clinical outcomes.

Gastric cancer (GC) ranks among the most prevalent malignant neoplasms globally and is one of the leading causes of cancer-related mortality. The gastric microbiota, as a crucial component of the human microecosystem, plays a pivotal role in maintaining human health through its ecological balance. In recent years, with the advancement of technologies such as metagenomics, the dysbiosis of gastric microbiota has increasingly become a focal point of research, particularly in understanding its role in the initiation, progression, and treatment of GC. This review elucidates the current understanding of the roles played by gastric microbiota and their metabolic products in the progression of GC. Additionally, it summarizes and prognosticates the translational value and clinical significance of gastric microbiota in the diagnosis, prognosis, and treatment of GC. The gastric microbiota assumes a dual role in the progression and treatment of GC. Further in-depth studies on the interactions and mechanisms between gastric microbiota and the host represent an emerging and valuable area in the field of GC research.

Background In recent years, tumor immunotherapy, exemplified by immune checkpoint inhibitors, has achieved remarkable success in certain patients. However, the efficacy of such therapies remains minimal in the majority of colorectal cancer patients. Overcoming the suppression of the tumor immune microenvironment and developing novel immunotherapeutic strategies have become focal points of research in this field. Adoptive cell therapy demonstrates immense potential, with chimeric antigen receptor macrophages exhibiting inherent advantages in combating solid tumors. GPA33, a surface antigen that is expressed in nearly all colorectal cancers, is a promising target for immunotherapy in colorectal cancer. This study aims to evaluate the potential therapeutic effects of GPA33-targeted CAR-macrophages in colorectal cancer. Methods Using single B cell isolation technology and single-cell PCR technology, we cloned the complete variable region sequences of mouse antibody light and heavy chains, which were subsequently employed to construct the scFv fragment of GPA33 CAR. CAR-Ms were generated by transfecting THP-1 cells with lentivirus, followed by PMA induction. The targeted phagocytic activity of CAR-Ms was observed using fluorescence microscopy, and their targeted phagocytosis, polarization trends, and tumoricidal effects were validated through flow cytometry. Cytokine secretion was quantified using ELISA assays. The in vitro and in vivo anti-tumor effects of CAR-Ms were assessed through bioluminescence measurements, while the safety of CAR-Ms was evaluated using HE staining and a small animal biochemical analyzer. Results Based on the successful development of a novel GPA33 antibody with high affinity and specificity, we constructed CAR-Ms targeting GPA33. For the in vitro experiments, GPA33-specific CAR-Ms were able to mediate antigen-dependent M1-like polarization of macrophages, enhancing their tumor phagocytic activity and pro-inflammatory cytokine secretion. In in vivo experiments, a xenograft model of colon cancer was established using immunodeficient mice, and the injection of CAR-Ms effectively inhibited tumor growth. Conclusions This study demonstrates that the GPA33 CAR-M, constructed based on a novel GPA33 antibody, exhibits significant inhibitory effects on GPA33 antigen-positive colorectal cancer. This finding offers a proof-of-concept for a potential strategy for immunotherapy in colorectal cancer.

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.

Gastric cancer (GC), a highly aggressive and heterogeneous malignancy, remains challenging in immunotherapy despite recent advancements. This study aims to identify novel biomarkers and construct a prognostic model to improve outcome prediction and therapeutic strategies. Mendelian randomization (MR) analysis identified immune cell subtypes linked to GC using FinnGen and GWAS cohorts. CIBERSORT and WGCNA algorithms were applied to define M2 tumor-associated macrophage (TAM)-related gene modules. Key prognostic genes were selected via Lasso-Cox regression to establish a risk model, validated using GEO datasets. Biological function disparities, tumor microenvironment heterogeneity, and therapeutic sensitivities were assessed via GSEA and immune infiltration analysis. Protein-level validation was performed using TCGA, HPA, and Western blot. MR analysis revealed 26 immune cell subtypes associated with GC. WGCNA identified 20 gene modules, with the most M2 TAM-correlated module prioritized. A prognostic signature incorporating SEC61G, BGN, and STC1 was developed, stratifying patients into distinct risk groups with divergent survival outcomes (1-/3-/5-year, all P < 0.05). High-risk patients exhibited enriched calcium signaling pathways, reduced immunotherapy responsiveness, and increased sensitivity to veriparib and palbociclib. Protein overexpression of key genes was validated in GC tissues. This integrated bioinformatics-MR framework establishes a TAM-driven prognostic model for GC, demonstrating clinical utility in survival prediction, immunotherapy efficacy evaluation, and personalized therapeutic targeting. The findings provide actionable insights for advancing precision immunotherapy in GC.