Research hotspots and frontiers in the tumor microenvironment of gastric cancer: a bibliometric review from 2005 to 2024

Introduction

Gastric cancer (GC) is a common and clinically significant gastrointestinal malignancy that remains a significant public health problem worldwide (1). With a delayed diagnosis and a lack of effective treatments, patients with progressive GC have poor outcomes, with a life expectancy of less than approximately one year (2). Common therapies for advanced GC include radiotherapy, chemotherapy, and targeted therapy (3). Over the past few years, immunotherapy has gradually advanced to the forefront of treatment, particularly when used in combination with chemotherapy, because it has been shown to improve therapeutic efficacy (4). Other types of immunotherapy, like chimeric antigen receptor-engineered T lymphocytes (CAR-T) cell therapy or cancer vaccines, are also under active investigation (5). The tumor microenvironment (TME) typically exhibits immunosuppressive properties, such as the ability to secrete immunosuppressive factors (TGF-β, IL-10) or myeloid-derived suppressor cells (MDSCs) and recruit regulatory T cells (Tregs), thereby hindering immune system attack (6).

TME is composed of tumor cells, immune cells, vascular endothelial cells, fibroblasts, and the extracellular matrix, among other components, and plays a central role in tumor initiation, development and resistance to treatment (7). An immunosuppressive state is often observed in the TME, which can reduce the effectiveness of immunotherapy. For example, tumor-associated macrophages (TAMs) help create an immunosuppressive microenvironment through various mechanisms, thereby reducing the efficacy of immunotherapeutic interventions (8). Metabolic reprogramming within the TME can also lead to immunosuppression, thereby limiting the effectiveness of programmed cell death protein 1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors (9). Immunotherapy efficacy may be enhanced by improving the TME, hydrogels can be utilized to modulate the TME, and proton pump inhibitors can be employed to remodel the acidic TME (10). Ferroptosis induction as a therapeutic strategy targeting TAMs is also a method under active exploration. Nanocarrier systems are capable of precisely delivering immunomodulatory drugs to tumor sites while simultaneously modulating the TME (11). The microbiota may have an impact on the immune microenvironment of tumors, representing a potential avenue for research (12). Anti-angiogenic therapies targeting the tumor vasculature have achieved some degree of success in certain cancers (13). Therapeutic strategies aimed at targeting the TME are designed to alleviate immunosuppressive conditions and transform the TME, thereby reactivating the immune response of the patient to maintain its antitumor efficacy.

Bibliometric analysis enables qualitative and quantitative assessment of publications within a database and the presentation of useful information from all relevant publications in the form of graphic charts and tables to reveal processes of development, hot topics and future trends in a given field. With the use of immune checkpoint inhibitors (ICIs) and other compounds in systemic therapy for advanced GC, researchers from different countries/regions have progressively increased their focus on the TME. Consequently, the number of TME-related publications related to GC has increased steadily from year to year. Nevertheless, bibliometric analysis of the TME in GC is lacking, and summaries of hot spots in research and forecasts of development trends in this area are lacking. In this study, we review the literature related to the TME in GC over the past two decades. We delve into current research hotspots and emerging topics in the field via bibliometric analysis. We present this article in accordance with the BIBLIO reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1211/rc).

Methods

Data collection

Our study conducted a comprehensive literature search via the Web of Science Core Collection (WOSCC), which is recognized as a premier academic database. As a repository of rigorously peer-reviewed journals, WOSCC’s selective coverage ensures the inclusion of high-calibre publications, rendering it particularly advantageous for bibliometric analysis when contrasted with alternative databases. This research exclusively analyzed journal articles published in English. The analysis was restricted exclusively to peer-reviewed research articles. The investigation focused on publications issued between the beginning of January 1, 2005, and the end of December 31, 2024. TS=(“Tumor Microenvironment*” OR “Cancer Microenvironment*” OR “Cellular Microenvironments” OR “Cell Microenvironment*”) AND TS=(“Stomach Neoplasm” OR “Gastric Neoplasm” OR “Cancer of Stomach” OR “Stomach Cancer” OR “Gastric Cancer” OR “Cancer of the Stomach”). Figure 1 presents a step-by-step visualization of the study selection procedure. The primary literature search was independently performed by two investigators (L.Z. and X.X.). Any discrepancies were resolved through discussion with a senior investigator (Y.W.) until consensus was achieved. The collected dataset encompassed publication counts, titles, authors, countries/regions, institutions, journals, highly cited articles, and keywords. WOSCC records were converted to plain text format and imported into CiteSpace v6.4 and VOSviewer v1.6.20 for analytical processing.

Figure 1 Schematic diagram of searching and screening documents.

Data analysis and visualization

Visual analysis in this research was conducted via three analytical tools: CiteSpace (v6.4), VOSviewer (v1.6.20), and Microsoft Excel 2021. CiteSpace is an essential tool for bibliometric and knowledge mapping research. Using CiteSpace, researchers can more efficiently uncover hidden information in the academic literature, providing support for scientific decision-making. The keyword analysis in this study was performed by employing CiteSpace software, thereby generating visual results. VOSviewer is a powerful and user-friendly tool for scientific literature analysis. We employ VOSviewer to examine the relationships among countries/regions, institutions, authors, references, and keyword cooccurrences.

Results

Annual number of publications

Our research identified 2,218 studies focusing on the TME in GC published between 2005 and 2024. Following the rigorous screening procedures shown in Figure 1, 1,486 articles met the eligibility criteria for the final analysis. The publication output demonstrated consistent annual growth throughout the study period, as illustrated in Figure 2, with the highest number of publications (n=305) occurring in 2024. This trend reflects increasing scholarly interest in the role of the TME in GC pathogenesis.

Figure 2 Annual publications on GC TME. GC, gastric cancer; TME, tumor microenvironment.

Analysis of countries

Global research on the TME in GC has involved scholars from 60 countries/regions during the last two decades. As presented in Table S1, China dominates the field with 1,098 publications, substantially surpassing the United States (n=155) and Japan (n=111). Notably, China’s publication output exceeds the aggregate output of the next nine most productive nations, potentially reflecting the country’s high GC burden. Chinese researchers have contributed disproportionately to this field, representing more than 60% of both total publications and citations. International collaboration patterns, analyzed through VOSviewer (Figure 3), reveal that the United States is the most connected nation (20 partners), followed closely by China (17 partners), highlighting their central roles in global research networks.

Figure 3 Cooperation between countries/regions based on VOSviewer.

Analysis of institutions

Institutional analysis revealed significant contributions from Chinese research centers, as detailed in Table S2. Nanjing Medical University emerged as the most productive institution (75 publications), followed by Fudan University (68 publications), Shanghai Jiao Tong University (67 publications), and Sun Yat-sen University (60 publications). Notably, all the top-ranking institutions originate from China, demonstrating the nation’s concentrated research efforts in GC. Our examination of 1,544 institutions identified 60 high-productivity centers (Figure 4), each contributing ≥10 publications. Collaboration network analysis through VOSviewer indicated Nanjing Medical University as the most connected institution, establishing partnerships with 31 other high-yield research centers.

Figure 4 Collaboration between institutions based on VOSviewer.

Analysis of authors

The analysis of author contributions (Table S3) identifies Zhang Xu as the most prolific researcher, with 20 publications, followed closely by Zhu Wei (19 publications) and Xu Wenrong (16 publications). Notably, Zhang Xu’s work has achieved the highest citation count (1,453 citations), demonstrating substantial academic influence within this research domain. These metrics suggest that these investigators may represent key opinion leaders in GC TME studies.

From the total pool of 10,641 contributing authors, we identified 219 highly productive researchers who met the minimum threshold of 5 publications each. Using VOSviewer, we analyzed co-authorship patterns among these high-yield authors. The network analysis revealed that Shi Min, as the most collaborative researcher, established connections with 18 other productive authors, as illustrated in Figure 5.

Figure 5 Collaboration between authors based on VOSviewer.

Journals and co-cited journals

Research on the GC TME appeared in 430 distinct journals between 2005 and 2024. As presented in Table S4, Frontiers in Oncology led journal productivity with 60 articles, followed by Frontiers in Immunology (49 articles) and Scientific Reports (31 articles). Collectively, the ten most active journals contributed 307 publications, representing 20.14% of the total output. Citation analysis revealed that Cancer Research was the most frequently referenced journal (2,300 citations), followed by Molecular Cancer (1,890 citations) and Oncotarget (1,235 citations). Notably, journals, including Cell Death & Disease and Cancer Immunology Immunotherapy, also demonstrated substantial influence through their citation frequency (Figure 6A).

Figure 6 The network of journal co-citation (A) and the dual-map of journals (B) in the field of TME in GC. In (A), circles represent journals, the size of the circle is proportional to the number of citations, and two connected circles represent a co-citation relationship between them. In (B), the left half is the citing journal map, the right half is the cited journal map, the curve connecting the two half maps is the citation path that shows the flow of knowledge and connections, and the circle represents the main cluster of citing or cited journals. GC, gastric cancer; TME, tumor microenvironment.

Figure 6B displays the dual-map overlay visualization of academic journals, illustrating the relationships between the journals. The citing journals are shown on the left, whereas the cited journals are displayed on the right. Research published in journals focusing on molecular/biology/genetics is frequently cited by journals focusing on medicine/medical/clinical and molecular/biology/immunology. The dual-map overlay in Figure 6B visually represents citation patterns between academic journals, with source publications appearing on the left and referenced journals on the right. Analysis revealed that studies originating from molecular/biology/genetics periodicals predominantly receive citations from publications in both clinical and molecular/biology/immunology.

Analysis of co-cited references

Co-citation analysis serves as an indicator of scholarly influence, occurring when multiple publications reference the same source. Articles receiving frequent citations from diverse research groups typically represent significant contributions to the field. To identify key research themes and influential works, we performed a co-citation analysis of the relevant literature. As shown in Table 1, the ten most cited publications [2005–2024] include the seminal 2020 study by Zhang et al. (781 citations), “m6A regulator-mediated methylation patterns and TME infiltration characterization in gastric cancer”, which demonstrated the crucial role of N6-methyladenosine (m6A) modification in shaping the heterogeneous TME in GC. This work currently has the highest citation count among the analyzed publications.

Keyword analysis

Keyword analysis was conducted after standardizing synonymous terms across the 1,486 included articles, yielding 4,786 unique keywords. To delineate research boundaries and identify focal points in GC TME studies, we established a minimum occurrence threshold of 20 instances, resulting in 104 high-frequency keywords for co-occurrence network analysis (Figure 7A). CiteSpace analysis revealed the top 20 keywords with the strongest citation bursts, organized by onset year, duration, and intensity. The visualization employs green lines to denote the study period [2005–2024] and red lines to highlight active burst periods. Notably, “growth” has attracted early and persistent research attention since 2014, reflecting its increasing relevance in hepatocellular carcinoma studies. Among immunology-related terms, “regulatory T cells” had the longest duration of citation bursts (Figure 7B), indicating an enduring scholarly focus on immunotherapeutic approaches.

Figure 7 Keywords of TME in GC. (A) Ranking by beginning. (B) Ranking by duration. (C) The connection between popular keywords. (D) Clustering of keywords over time, presented as a map. (E) Landscape view; the horizontal axis represents time, and the height of the “peaks” typically indicates the research intensity of a topic. CCs, connected components; CST, China standard time; GC, gastric cancer; L/N, links per node; LBY, look back years; LRF, link retaining factor; TME, tumor microenvironment.

Keyword clustering analysis, visualized through VOSviewer (Figure 7C), revealed four distinct thematic groups differentiated by color coding. Each cluster’s research focus was identified by analyzing both keyword frequency distributions and average publication years within the respective groups. The major roles in the TME of GC are represented by red clusters, such as “immunotherapy”, “nivolumab” and “chemotherapy”; green clusters represent progress in GC, such as “promotes”, “invasion” and “metastasis”; yellow clusters represent macrophages in GC, such as “tumor-associated macrophages”, “activation” and “polarization”; and blue clusters represent immune cell infiltration in GC, such as “lymphocytes”, “T-cells” and “dendritic cells”. As demonstrated in Figure 7D,7E, related keywords such as “tumor microenvironment” began to emerge approximately 2010. Subsequently, “immunotherapy” emerged in 2017. This served as the foundation for this study and continued to be at the forefront of research throughout the study.

Key components

TAMs

As versatile components of the immune system, macrophages perform multiple physiological roles, including maintenance of tissue equilibrium, antimicrobial defense mechanisms, and tissue repair processes (14-16). Within the TME, resident macrophages—termed TAMs—exhibit phenotypic plasticity. These cells undergo polarization into two functionally distinct subsets (M1 and M2) depending on the cytokine milieu. Exposure to inflammatory stimuli, including microbial components (e.g., lipopolysaccharide) or T helper 1 cells (Th1) cytokines (e.g., interferon-gamma), induces differentiation toward the M1 phenotype (17). M1-polarized TAM subset has increased secretion of proinflammatory mediators, including interleukin-12 (IL-12), interleukin-23 (IL-23), and tumor necrosis factor-alpha (TNF-α), consequently exerting antitumor effects through cytokine-mediated pathways (18). M1-polarized TAMs recruit cytotoxic CD8⁺ T lymphocytes to gastric tumor sites via chemokine signaling pathways, particularly through interactions between the C-X-C chemokine receptor type 3 (CXCR3) receptor and its ligands (CXCL9, CXCL10, and CXCL11), thereby enhancing antitumor immunity against malignant cells (19). M2-polarized macrophages, which are stimulated by interleukin-4 (IL-4) and interleukin-13 (IL-13), contribute to tumor progression through multiple mechanisms, including tissue remodeling and facilitating neoplastic expansion (20,21). TAMs exhibit remarkable phenotypic plasticity and are capable of transitioning between proinflammatory (M1) and immunosuppressive (M2) states. In GC, these cells predominantly adopt the M2 phenotype, which is correlated with an unfavorable clinical prognosis (22). Recent therapeutic strategies have increasingly focused on modulating TAMs through multiple approaches: suppression of M2-like polarization, phenotypic reprogramming toward antitumor M1 states, and synergistic combination with existing immunotherapies such as checkpoint inhibition (23,24). Emerging therapeutic approaches have been significantly enhanced through three key developments: nanoscale delivery systems, metabolic pathway modulation, and targeted intervention of critical signaling axes, including the IL-6 and CCL2/CCR2 pathways (20,25-27).

Cytotoxic T lymphocytes

CD8⁺ T cells have cytotoxic capabilities that allow them to recognize and eliminate cells that have been infected by a pathogen or that have undergone cancerous transformation (28). The TME represents a sophisticated biological network in which cytotoxic CD8⁺ T lymphocytes serve as crucial mediators of antitumor immunity (29). The density and distribution patterns of tumor-infiltrating CD8⁺ T lymphocytes are significantly correlated with clinical outcomes during GC progression and serve as valuable prognostic indicators (30). CD8⁺ T cell subset with high expression of CD161 is significantly enriched in chemotherapy-resistant gastric tumors and has the capacity to inhibit calcium influx and T cell functionality; this property contributes to the promotion of immune evasion within these tumor contexts (31). ICIs exert their therapeutic effects through blockade of key regulatory molecules, including PD-1/PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This molecular interference releases T-cell inhibitory signals and potentiates their tumoricidal capacity, resulting in clinically significant responses in certain patient populations (32,33). While significant advances have been made in T cell-based oncological research and treatment, the complex regulatory networks governing T cell behavior in malignant microenvironments remain incompletely understood. Current immunotherapeutic approaches demonstrate substantial interpatient response heterogeneity, highlighting the urgent need for reliable predictive biomarkers to identify potential treatment responders.

Natural killer (NK) cells

NK cells possess the innate capacity to identify and eliminate malignant or infected cells independently of antigen-specific priming (34). NK cells execute their tumoricidal function through two principal mechanisms: secretion of cytotoxic granules containing perforin and granzyme proteases and facilitation of antibody-dependent cellular cytotoxicity (ADCC) through Fc receptor engagement (35-37). In the GC microenvironment, gastric cancer mesenchymal stem cells (GCMSCs) suppress NK cell function, fructose-1,6-bisphosphatase 1 (FBP1) upregulation attenuates cytotoxic granule release and perforin synthesis, and metabolic interference reduces glycolytic flux by diminishing glucose utilization and lactate production in NK cells (38). Studies have shown elevated NK cell levels in those with GC compared with those with ulcers, but these cells are linked to a lower survival rate (39,40). Current clinical investigations suggest that incorporating NK cell immunotherapy with standard chemotherapeutic regimens may enhance treatment efficacy against gastric malignancies (41). Despite promising antitumor activity, NK cell-based therapies face several translational challenges, including the identification of optimal cellular sources, the development of reliable expansion protocols, and the standardization of therapeutic dosing regimens. The antitumor efficacy of NK cells is significantly constrained by the immunosuppressive evasion strategies employed within the malignant niche (42).

Dendritic cells (DCs)

As essential mediators of adaptive immunity, DCs function as professional antigen-presenting cells that orchestrate crucial antitumor immune responses (43). Within the gastric TME, cancer-associated fibroblasts actively produce wnt family member 2 (WNT2), impairing DC maturation and activity via activation of the suppressor of cytokine signaling 3 (SOCS3)-mediated Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) phosphorylation cascade. This immunosuppressive mechanism leads to decreased infiltration of functionally competent cytotoxic T lymphocytes, consequently facilitating immune evasion by malignant cells (44). Plasmacytoid dendritic cells (pDCs) contribute to tumor immune tolerance by activating immunosuppressive Treg populations via inducible T-cell co-stimulator (ICOS) ligand-mediated signaling. This pDC-Treg axis has been functionally linked to enhanced neoplastic progression through its suppressive effects on antitumor immunity (45). DC-based vaccines incorporating tumor-associated antigens have exhibited promising therapeutic efficacy across multiple cancer types (46). The efficacy of DC vaccines in clinical trials is suboptimal because of ineffective immunogenicity and the use of biomarkers for patient selection. Research has focused on improving the immunogenicity of DC vaccines, but no breakthroughs have been achieved. Additionally, preclinical models that are not accurate for current clinical applications of DC vaccines face two major limitations: inadequate immune stimulation, a lack of reliable predictive biomarkers, and poor translatability from animal models to human patients. While significant research efforts have aimed to increase vaccine immunogenicity, substantial improvements in clinical outcomes remain unrealized. reflects the actual clinical scenario (47).

Immunotherapy in GC

CAR-T

CAR-T cells represent a genetically modified immunotherapeutic approach in which T cells are reprogrammed to express synthetic receptors capable of precise tumor antigen recognition and malignant cell targeting (48). Immunosuppressive nature of the malignant niche may constrain the therapeutic effectiveness of chimeric antigen receptor T-cell interventions (49). Immunosuppressive mediators within the malignant niche have been shown to significantly impair the antitumor activity of CAR-T (50,51). Recent advances in GC immunotherapy have demonstrated the clinical potential of antigen-specific CAR-T cell approaches. Notably, Claudin18.2-targeted CAR-T cells (CT041) achieved a complete radiographic response in metastatic lesions, maintaining partial tumor regression for eight months. Treatment efficacy was further supported by reduced circulating tumor DNA levels and a favorable safety profile devoid of grade ≥3 adverse events (52). c-Met-specific chimeric antigen receptor T cells demonstrated robust cytotoxic effects against c-Met-expressing gastric malignancies in preclinical studies. These engineered lymphocytes effectively suppress tumor progression in animal models while maintaining target specificity. Genetic modification with a PD-1/CD28 chimeric switch receptor augments their therapeutic potential by enhancing tumoricidal activity, attenuating interleukin-6 production, and mitigating the risk of cytokine release syndrome (53).

Chimeric antigen receptor T-cell immunotherapy has established itself as a transformative approach in oncology, showing remarkable clinical responses—especially for hematological cancers—in which treated individuals have achieved durable complete remission (54). Current investigations are exploring the therapeutic applications of CAR-T-cell-derived exosomes as a novel immunotherapeutic strategy against malignancies (55). The application of CAR-T cell therapy against solid malignancies faces immunological barriers, such as tumor immune evasion mechanisms that circumvent T cell recognition and antigen escape phenomena involving either target antigen downregulation or presentation alterations (56). Furthermore, CAR-T cells themselves are susceptible to exhaustion, resulting in a reduction in their antitumor efficacy over time (57).

ICIs

ICIs represent a class of immunomodulatory drugs that potentiate antitumor responses through blockade of key regulatory pathways. These agents specifically inhibit negative immune regulators, including PD-1, PD-L1, and CTLA-4, thereby releasing T cell inhibitory signals and augmenting their cytotoxic activity against malignant cells, ultimately resulting in tumor shrinkage (58). The clinical application of ICIs in gastric carcinoma has shown measurable therapeutic benefits, particularly for advanced-stage disease. These immunotherapeutic agents significantly prolong overall survival and increase tumor response rates in patients with metastatic disease. Representative PD-1 inhibitors, including nivolumab and pembrolizumab, have demonstrated clinically meaningful improvements in treatment outcomes for refractory GC patients (59). PD-1, a 55 kDa immunoglobulin superfamily member, functions as a critical immune checkpoint regulator expressed on activated lymphocytes and myeloid cells. This type I transmembrane protein modulates immune homeostasis by preventing excessive immune activation and maintaining peripheral tolerance. In oncogenesis, PD-1 signaling facilitates tumor immune evasion across multiple malignancies. Its primary ligand PD-L1 (33 kDa), similar to a type I membrane protein, is expressed inducibly on both immune and neoplastic cells during inflammation. The PD-1/PD-L1 axis promotes oncogenic processes through the activation of proliferative and antiapoptotic pathways, the induction of mesenchymal transition, and the enhancement of cancer stem cell properties (60).

Within malignant tissues, neoplastic cells exploit the PD-L1/PD-1 axis as an immune escape mechanism. Through ligand‒receptor interactions, tumor-expressed PD-L1 engages PD-1 receptors on T lymphocytes, initiating downstream signaling, attenuating T cell activation, inhibiting clonal expansion, reducing cytotoxic mediator release and impairing lymphocyte survival (61). Elevated PD-L1 expression serves as a prognostic biomarker for aggressive disease progression in certain gastric adenocarcinoma subtypes, with clinical evidence linking its overexpression to decreased patient survival. At the molecular level, the Helicobacter pylori oncoprotein CagA orchestrates a sophisticated immunosuppressive program by hijacking the p53-miR-34a axis to amplify exosomal PD-L1 cargo. This pathogenic rewiring of intercellular communication cripples antitumor immunity through concerted suppression of cytotoxic T cell responses—blunting lymphocyte proliferation, silencing inflammatory cytokine networks, and ultimately fostering an immune-permissive niche that drives malignant advancement (62). The rs17718883 genetic variant (P146R substitution) in gastric carcinoma patients produces a paradoxical clinical phenotype: while impairing PD-L1/PD-1 binding and conferring resistance to checkpoint inhibition, this polymorphism is correlated with reduced cancer risk and improved survival outcomes (63). Emerging evidence highlights a critical role for macrophage polarization states in modulating the response to immune checkpoint inhibition. While proinflammatory M1-polarized macrophages enhance antitumor immunity through chemokine-mediated recruitment of cytotoxic CD8⁺ T lymphocytes, the gastric TME is predominantly infiltrated by pro-tumoral M2-like variants that promote malignant progression. This biological dichotomy suggests that therapeutic macrophage repolarization toward the M1 phenotype could synergize with PD-1/PD-L1 blockade to overcome immune resistance (64). Fecal microbiota transplantation could potentiate ICI responses through microbial community modulation (65). Several molecular characteristics, including specific transcriptional profiles and tumor mutation loads, show potential as predictive indicators for the ICI response, although their clinical utility necessitates additional rigorous verification (66).

Oncolytic viruses

Oncolytic virotherapy employs either naturally selective or genetically modified viral strains that preferentially infect and destroy malignant cells while sparing healthy tissues. These therapeutic agents exert dual antitumor effects through direct cytolytic activity and the induction of systemic tumor-specific immunity (67). Oncolytic viruses orchestrate complex remodeling of the TME through specialized enzymatic machinery, as exemplified by hyaluronidase-expressing strains such as OVV-Hyal1. By enzymatically dismantling hyaluronic acid networks, these therapeutic vectors simultaneously achieve three therapeutic advantages: enhanced viral propagation through tissue barriers, improved chemotherapeutic penetration, and facilitated immune cell infiltration—effectively converting immunologically “cold” tumors into treatment-responsive ecosystems (68). Oncolytic virotherapy demonstrates immunomodulatory capacity through the regulation of checkpoint molecule expression, with combinatorial approaches employing immune checkpoint blockade showing synergistic enhancement of antitumor activity (69). Oncolytic virotherapy has emerged as a promising therapeutic strategy for multiple malignancies, particularly melanoma and gastric carcinoma. Clinical data reveal that both standalone administration and combination regimens can yield meaningful clinical benefits, including prolonged survival duration and improved patient-reported outcomes in responsive individuals (70). CF17 treatment significantly improved survival outcomes in mice with peritoneal metastasis of GC (71). CF33 and its derivative CF33-hNIS-anti-PD-L1 exhibit cytotoxic effects against GC cells in vitro without demonstrating significant off-target toxicity (72). Oncolytic viruses represent a promising therapeutic strategy; however, some patients exhibit insensitivity to oncolytic virus therapy, potentially because the virus’s immunogenicity leads to premature clearance by the body or the low susceptibility of tumor cells to the virus (73,74). Current research is predominantly in the preclinical or early clinical trial stages and lacks large-scale, multicenter clinical trial data to support its efficacy (75). The production, storage, and transportation of oncolytic viruses present technical challenges, all of which limit their widespread application.

RNA methylations in GC

Among eukaryotic RNA modifications, m6A represents the most abundant and evolutionarily conserved epigenetic marker (76). This epigenetic mark governs critical posttranscriptional regulatory mechanisms, including messenger RNA processing, degradation kinetics, and translational control, thereby influencing diverse physiological and pathological states. The methylation reaction is mediated by a conserved methyltransferase complex comprising METTL3-METTL14 heterodimers, which function as the primary enzymatic writers of this modification (77). m6A modification is dynamically reversible through the activity of specific demethylase enzymes, including ALKBH5, which functions as molecular erasers to precisely remove this epigenetic mark (78), and is recognized by “readers”, such as YTH family proteins (79). The m6A-binding protein YTHDF2 selectively targets m6A-modified transcripts for degradation, thereby modulating critical oncogenic processes, including neoplastic cell proliferation and metastatic dissemination (80). Alterations in m6A methylation patterns within malignant cells can modulate the transcriptional regulation of immune checkpoint proteins, consequently reshaping the immunomodulatory landscape of the TME (81). Specific m6A-modified long noncoding RNAs demonstrate significant prognostic relevance in gastric adenocarcinoma, serving as potential biomarkers for clinical outcomes (81), epitranscriptomic regulation mediated by m6A methylation can modulate chemotherapeutic response patterns in gastric malignancies, potentially serving as a determinant of treatment efficacy (82), it can be used to predict patients’ responses to treatment, providing a basis for personalized therapy.

Discussion

General information

In this research, we systematically examined the global scholarly output on the TME of patients with GC over a 20-year period [2005–2024] via WOSCC data. Following rigorous screening protocols, we analyzed 1,486 qualifying articles published across 430 journals. The dataset encompassed contributions from 10,641 researchers affiliated with 1,544 institutions spanning 60 nations. The publication trends demonstrated consistent annual growth, with a notable surge exceeding 250 articles annually in recent years. This pattern reflects the growing scientific consensus regarding the critical role of the TME in GC pathogenesis and therapeutic development.

A comprehensive analysis of the extant literature suggests that China is the global leader in this domain, followed closely by the United States and Japan, in second and third positions. It is imperative to accentuate the observation that the aggregate number of publications and citations emanating from China surpasses the sum of those emanating from other countries/regions (Table S1). Furthermore, an examination by Tables S2,S3 reveals that China has the top ten research institutions and that most scholars have the highest publication outputs. China’s substantial research investment in this field likely reflects its disproportionate share of global GC cases, representing 44% of the worldwide disease burden (83). Chinese institutions and scientists are working to increase survival and improve prognosis by researching this disease. While leading in publication output among all the institutions examined, Nanjing Medical University demonstrates particular research dominance in this field, but Shanghai Jiao Tong University is cited more than twice as often as Nanjing Medical University is. These findings underscore Shanghai Jiao Tong University’s prominent contributions to this research domain. The majority of the institutional cooperation network is dominated by Chinese institutes, whereas institutes from foreign countries are marginal and of lower centrality, reflecting the low level of international institutional cooperation. As a result, to better promote the development of this field, institutions should transcend regional constraints and strengthen international cooperation. As the most prolific and highly cited researcher in this domain, Zhang Xu has emerged as a leading authority. This prominence reflects the crucial involvement of immune components, particularly N2 tumor-associated neutrophils and mesenchymal stem cells, in the dynamics of the GC microenvironment, tumor progression, and diagnostic applications (84-86).

Types of research publications are reflected in academic journals. Among the 430 journals, Frontiers in Oncology published the most articles, followed by Frontiers in Immunology; as a result, the focus of research may be in the area of immunology. Only two of the top ten journals belong to the Q2 journal citation reports (JCR), whereas all others belong to the Q1 JCR, as shown in Table S4. However, the journals’ impact factors are low, confirming that work still needs to be done to improve the quality of the scholarship produced in this area. Zhang Bo’s paper “m6A regulator-mediated methylation patterns and TME infiltration characterization in gastric cancer”, published in Molecular Cancer in 2020, is the most cited paper. Through the analysis of 1,938 GC samples, this investigation elucidated the associations between m6A methylation profiles and TME infiltration patterns. The developed m6A score quantification system enables the evaluation of individual tumor modification characteristics, suggesting potential clinical utility for immunotherapy optimization.

Scientific implications and evolving trends

This bibliometric review systematically delineates the evolution and structural characteristics of research on the TME in GC from 2005 to 2024. In terms of scientific implications, the field has established mature research directions, exemplified by immune checkpoint blockade, which has demonstrated clear clinical efficacy. Meanwhile, emerging immunotherapies such as CAR-T and oncolytic virotherapy show promise but still face challenges posed by the suppressive solid TME. Notably, nascent fields including epigenetic regulation (e.g., m6A methylation), computational oncology (e.g., machine learning), and metastatic microenvironment mechanisms are rapidly emerging, representing a critical shift from descriptive studies to mechanistic dissection and precision intervention. These trends collectively outline the future trajectory of GC TME research, evolving from immunotherapy towards multi-omics integration and intelligent analysis, thereby providing a theoretical foundation and methodological support for developing individualized treatment strategies.

Limitations

Several methodological constraints should be acknowledged in this investigation. The technical limitations of bibliometric visualization tools currently preclude comprehensive cross-database analysis, necessitating exclusive reliance on WOSCC despite its recognized predominance in bibliometric studies. This approach may exclude pertinent publications indexed in alternative repositories such as PubMed or Scopus. Furthermore, the language restriction to English-language articles potentially omits clinically relevant findings from high-incidence regions where GC research is frequently published in local journals. Future advancements in bibliographic analytic methods may enable the incorporation of multilingual datasets across multiple platforms, yielding more representative and geographically balanced scientific assessments.

Conclusions

This systematic bibliometric evaluation delineates the evolving landscape of GC microenvironment research from 2005 to 2024, revealing three transformative immunotherapeutic frontiers: chimeric antigen receptor T-cell technology, immune checkpoint blockade, and oncolytic virotherapy. Cutting-edge investigations into TME biology are paving the way for precision medicine approaches in gastric oncology. Emerging therapeutic strategies targeting microenvironmental components, including CAR-T interventions and macrophage reprogramming, hold significant potential for clinical advancement. The analysis also identified novel research directions, particularly in epigenetic regulation (m6A methylation), computational oncology (machine learning applications), and metastatic niche biology (hepatic dissemination patterns). Collectively, these findings establish a conceptual framework for TME investigations, highlight current research priorities, and offer valuable insights to guide future scientific exploration of GC therapeutics.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the BIBLIO reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1211/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1211/prf

Funding: This research was supported by the National Natural Science Foundation of China (No. 82360498); Gansu Joint Scientific Research Fund Major Project (No. 23JRRA1537); The 2025 Central-Guided Local Science and Technology Development Found (No. 25ZYJA003); Gansu Provincial Health Industry Science and Technology Innovation Major Project (No. GSWSZD2024-01); and Gansu Province Key Talent Project (No. 2025RCXM067).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1211/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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