Abstract
Background
Tumor-associated macrophages (TAMs) are key regulators of the esophageal cancer microenvironment and are increasingly implicated in immune suppression, tumor invasion, metastasis, and therapeutic resistance. With the rapid expansion of immunotherapy research and high-dimensional profiling technologies, a systematic and quantitative overview of this field is needed. Therefore, this study aimed to characterize the global research landscape, identify major hotspots, and explore emerging trends in TAM-related esophageal cancer research.
Methods
Publications on macrophages in esophageal cancer indexed in the Web of Science Core Collection (WoSCC) from 2000 to 2025 were retrieved using predefined topic-search terms and eligibility criteria. Full records and cited references were exported and analyzed using GraphPad Prism for descriptive statistics, VOSviewer for keyword co-occurrence mapping, and CiteSpace for collaboration networks, co-citation analysis, clustering/timeline visualization, and burst detection.
Results
A total of 486 records were included, involving 38 countries/regions, 614 institutions, and 3,108 authors. Publication output increased gradually after 2000, accelerated after 2014, and continued to rise after 2020. Co-citation analysis identified a knowledge base centered on immunosuppressive microenvironment mapping in esophageal squamous cell carcinoma (ESCC) and pivotal phase III immunotherapy evidence. Keyword mapping highlighted core themes of TAMs, prognosis, and the tumor microenvironment, with recent clusters and burst signals emphasizing immunotherapy, immune signatures, and single-cell transcriptomics.
Conclusions
Macrophage-related research in esophageal cancer has shifted from early inflammatory characterization toward mechanistic and clinically oriented studies focused on immune regulation and treatment response. Emerging fronts-including state-resolved TAM biology, immune-signature modeling, and single-cell/spatial approaches are likely to guide future work and inform macrophage-targeted combination strategies with checkpoint blockade.
Keywords: Esophageal cancer, tumor-associated macrophages (TAMs), tumor microenvironment, immunotherapy, bibliometric analysis
Highlight box.
Key findings
• A bibliometric and visualization analysis of macrophage-associated research in esophageal cancer (Web of Science Core Collection, 2000–2025; n=486) identified influential contributors, knowledge bases, and rapidly emerging themes.
• The research focus has shifted from inflammation-related descriptions toward immunotherapy-oriented and high-dimensional profiling topics.
What is known and what is new?
• Tumor-associated macrophages (TAMs) are central regulators of tumor progression, immune suppression, and therapy resistance in esophageal cancer, and related publications have increased substantially.
• This study provides a structured map of the field using co-authorship, co-citation, keyword clustering, timeline evolution, and burst detection, clarifying how the intellectual landscape has evolved and where current frontiers are concentrated.
What is the implication, and what should change now?
• The identified hotspots suggest prioritizing TAM-focused translational studies that integrate immunotherapy, immune phenotyping, and single-cell/spatial technologies.
• These findings can guide researchers and clinicians to target high-impact directions, foster collaboration, and design macrophage-centered combination strategies in thoracic oncology.
Introduction
Tumor-associated macrophages (TAMs) are increasingly recognized as key architects of the esophageal cancer microenvironment, shaping immune suppression, angiogenesis, invasion, and therapeutic resistance (1,2). In esophageal squamous cell carcinoma (ESCC) and adenocarcinoma, macrophage plasticity and macrophage-lymphocyte crosstalk influence both prognosis and response to systemic therapies, particularly as immune checkpoint inhibitors have become integrated into standard treatment paradigms (3,4). Concurrently, high-dimensional technologies, such as single-cell RNA sequencing and immune-signature modeling, have expanded mechanistic inquiry and accelerated translational outputs (5-7). As a result, the literature on macrophages in esophageal cancer has grown rapidly and diversified into multiple, partially overlapping research fronts (8).
As the field expands, it becomes difficult to track its development using narrative reviews alone. Important questions include how publication output has changed over time, which countries, institutions, journals, and authors have driven progress, what studies constitute the intellectual base of the field, and which topics are emerging as new hotspots (9). Bibliometric analysis provides a quantitative framework to address these questions by combining publication metadata with cited-reference relationships (10,11). Co-authorship and collaboration networks reflect the social structure of research, co-citation analysis identifies foundational and influential work, and keyword co-occurrence and burst detection help characterize thematic structure and its evolution.
In this study, we performed a bibliometric and visualization analysis of macrophage-related research in esophageal cancer indexed in the Web of Science Core Collection (WoSCC) from 2000 to 2025. Using standardized retrieval and export of full records and cited references, we assessed publication trends and mapped collaboration patterns, co-citation structures, and keyword dynamics with GraphPad Prism, CiteSpace, and VOSviewer. This work provides an overview of how the field has developed, highlights influential contributors and core references, and summarizes the main research themes and emerging directions. We present this article in accordance with the BIBLIO reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2781/rc).
Methods
Data acquisition
WoSCC is widely regarded as the optimal database for bibliometric analysis because its document-type labeling is considered more accurate than that of other databases (12,13). Therefore, we selected WoSCC for literature retrieval. On December 11, 2025, we searched the WoSCC for all publications related to macrophages in esophageal cancer published between January 1, 2000 and December 1, 2025, using the following query: ((((((((TS=(“Esophageal Neoplasm”)) OR TS=(“Neoplasm, Esophageal”)) OR TS=(“Esophagus Neoplasm”)) OR TS=(“Cancer of Esophagus”)) OR TS=(“Esophageal Cancer”)) OR TS=(“Cancer of the Esophagus”)) OR TS=(“Esophageal Squamous Cell Carcinoma”)) OR TS=(“Oesophageal Squamous Cell Carcinoma”)) OR TS=(ESCC)) AND TS=(macrophage)). Publications were screened according to the following inclusion criteria: (I) full-text publications relevant to macrophages in esophageal cancer; (II) documents classified as articles or reviews, written in English; and (III) publications released between January 1, 2000 and December 11, 2025. The exclusion criteria were: (I) studies irrelevant to macrophages in esophageal cancer; and (II) document types such as meeting abstracts, news, and brief reports. The records were exported in plain text format and this bibliometric study flow gram is shown in Figure 1.
Figure 1.
Flowchart of literature search. WoSCC, Web of Science Core Collection.
Data analysis and visualization
Data analysis and visualization were performed using GraphPad Prism (v8.0.2), CiteSpace (v6.2.4R, 64-bit Advanced Edition), and VOSviewer (v1.6.18). These tools were applied to assess annual publication output, national publication trends, and related proportions, and to construct scientific knowledge maps. We used GraphPad Prism v8.0.2 to analyze and visualize annual publication outputs, national publication trends, and publication proportions (14). To visualize research outputs within a field through co-citation networks, Professor Chaomei Chen developed CiteSpace (v6.2.4R), which is designed as an experimental framework for exploring emerging concepts and evaluating existing knowledge structures (15). VOSviewer, developed by van Eck et al. in 2010, is a free Java-based software tool for analyzing large-scale bibliometric data and presenting the results in map-based visualizations (16). In VOSviewer, the minimum keyword co-occurrence threshold was set to 8. Mapping was performed using the default association strength normalization with default layout settings. In CiteSpace, analyses were conducted for 2000–2025 with a 1-year time slice, using the default term source and a single node type per run. Nodes were selected using the g-index (k =25), with all other parameters kept at default values. Clustering was performed using the “all in one” approach via the cluster function, with layout and style adjusted for improved readability; clusters were labeled by “Keywords” and generated using the log-likelihood ratio (LLR) method. For citation burst detection, γ was set to 0.1 with a minimum burst duration of 1 year; all other parameters remained at default, and the top 50 burst keywords were retained for subsequent analyses. Collectively, these tools supported multidimensional bibliometric mapping and visualization, allowing us to characterize publication patterns, detect emerging themes, and delineate collaboration networks, thereby identifying core topics and potential future directions in this field. This study was conducted in accordance with the BIBLIO guidelines for reporting bibliometric reviews of biomedical literature (17).
Results
Global trend in publication outputs and citations
The results showed that, from January 1, 2000 to December 11, 2025, a total of 486 publications on macrophages in esophageal cancer were retrieved from the WoSCC database. These studies involved 38 countries/regions, 614 institutions, and 3,108 authors. Since 2000, the annual number of publications has increased gradually (Figure 2). We further divided the trend into three periods: 2000–2013, characterized by slow growth with approximately 10 publications per year, suggesting limited attention to this topic; 2014–2020, during which publications rose rapidly, indicating accelerated development of the field; and after 2020, when the annual output continued to increase, reaching its peak in 2025.
Figure 2.
Published trend chart concerning macrophage-related research in esophageal cancer.
Distribution of countries/regions
A total of 38 countries/regions have conducted research on macrophages in esophageal cancer. Figure 3A,3B present the annual publication outputs of the top 10 countries over the past decade. The five most productive countries in this field were China, Japan, Canada, and Germany. China contributed 68.31% of all publications, far exceeding other countries. Among the top 10 countries/regions by publication count, China’s publications received 6,938 citations (Table 1), substantially more than any other country/region; however, its citations-per-publication ratio (20.90) ranked ninth, suggesting an overall relatively lower average citation impact. Japan ranked second in publication output (84 papers) and second in total citations (n=3,356), with a relatively high citations-per-publication ratio (39.95).
Figure 3.
Country/region collaboration patterns in macrophage-focused esophageal cancer research. (A) Publication trends over time by country. (B) Country-level output displayed as a heat map. (C) Cross-country collaboration map, where node size reflects publication volume and edge color indicates the collaboration year.
Table 1. Table of country published literature.
| Rank | Country/region | Article counts | Centrality | Percentage (%) | Citation | Citation per publication |
|---|---|---|---|---|---|---|
| 1 | China | 332 | 0.31 | 68.31 | 6,938 | 20.90 |
| 2 | Japan | 84 | 0.01 | 17.28 | 3,356 | 39.95 |
| 3 | USA | 52 | 0.41 | 10.70 | 2,769 | 53.25 |
| 4 | Germany | 11 | 0.06 | 2.26 | 206 | 18.73 |
| 5 | Italy | 8 | 0.08 | 1.65 | 420 | 52.50 |
| 6 | The Netherlands | 6 | 0.02 | 1.23 | 172 | 28.67 |
| 7 | Canada | 6 | 0 | 1.23 | 331 | 55.17 |
| 8 | Australia | 6 | 0 | 1.23 | 209 | 34.83 |
| 9 | South Korea | 5 | 0 | 1.03 | 125 | 25.00 |
| 10 | England | 3 | 0.02 | 0.62 | 220 | 73.33 |
As shown in the collaboration network (Figure 3C), the two most productive countries, China and Japan, exhibited close collaboration. China also collaborated extensively with the USA, Australia, and Italy, whereas Japan showed stronger collaboration with Germany, The Netherlands, and South Korea. China not only demonstrated the highest publication output and citation frequency, but also showed a centrality value of 0.31, indicating its leading role in the field.
Institutions
A total of 614 institutions have systematically published studies on macrophages in esophageal cancer. Among the top 10 most productive institutions, nine were from China and one was from Japan (Table 2; Figure 4). Zhengzhou University ranked first, with 41 publications and 917 citations (22.37 citations per paper). Sun Yat-sen University ranked second (40 publications, 895 citations, 22.38 citations per paper), followed by the Chinese Academy of Medical Sciences-Peking Union Medical College (36 publications, 805 citations, 22.36 citations per paper). State Key Laboratory of Oncology in South China ranked fourth (27 publications, 554 citations, 20.52 citations per paper). Further analysis indicated that both domestic and international institutions tended to collaborate primarily with partners within their own countries. Therefore, we call for strengthened cross-national and cross-institutional collaborations to help reduce academic barriers.
Table 2. Table of institutional published literature.
| Rank | Institution | Country | Number of studies | Total citations | Average citation |
|---|---|---|---|---|---|
| 1 | Zhengzhou University | China | 41 | 917 | 22.37 |
| 2 | Sun Yat-sen University | China | 40 | 895 | 22.38 |
| 3 | Chinese Academy of Medical Sciences-Peking Union Medical College | China | 36 | 805 | 22.36 |
| 4 | State Key Lab Oncology South China | China | 27 | 554 | 20.52 |
| 5 | Peking Union Medical College | China | 22 | 534 | 24.27 |
| 6 | Kobe University | Japan | 20 | 459 | 22.95 |
| 7 | Capital Medical University | China | 19 | 239 | 12.58 |
| 8 | Cancer Institute & Hospital-CAMS | China | 18 | 320 | 17.78 |
| 9 | Fudan University | China | 17 | 502 | 29.53 |
| 10 | Nanjing Medical University | China | 16 | 175 | 10.94 |
CAMS, Chinese Academy of Medical Sciences.
Figure 4.
International collaboration network of institutional co-operation.
Journals
Tables 3,4 summarize the top 10 journals ranked by publication output and total citations, respectively. Frontiers in Immunology (22 articles, 4.53%) published the largest number of papers in this field, followed by Frontiers in Oncology (16 articles, 3.29%), Cancer Science (10 articles, 2.06%), and Discover Oncology (9 articles, 1.85%) (Figure 5A). Among the top 10 most productive journals, Cancer Letters had the highest impact factor (IF =10.1), and 90% of these journals were classified as Q1 or Q2. Journal influence is often reflected by co-citation frequency, indicating whether a journal has had substantial impact within the scientific community. As shown in Figure 5B and Table 4, the most frequently co-cited journal was Cancer Research (301 co-citations), followed by Clinical Cancer Research (235 co-citations) and Cell (228 co-citations). Within the top 10 co-cited journals, CA: A Cancer Journal for Clinicians was co-cited 208 times and had the highest IF (IF =232.5). Of the co-cited journals, 90% were also ranked in Q1/Q2.
Table 3. Journals publications literature.
| Rank | Journal | Article counts | Percentage (%) | IF | Quartile in category |
|---|---|---|---|---|---|
| 1 | Front Immunol | 22 | 4.53 | 5.9 | Q1 |
| 2 | Front Oncol | 16 | 3.29 | 3.3 | Q2 |
| 3 | Cancer Sci | 10 | 2.06 | 4.3 | Q2 |
| 4 | Discov Oncol | 9 | 1.85 | 2.9 | Q2 |
| 5 | Cancer Immunol Immunother | 8 | 1.65 | 5.1 | Q1 |
| 6 | Cancer Lett | 8 | 1.65 | 10.1 | Q1 |
| 7 | Oncotarget | 8 | 1.65 | – | – |
| 8 | J Cancer | 7 | 1.44 | 3.2 | Q2 |
| 9 | Cancers | 6 | 1.23 | 4.4 | Q2 |
| 10 | Int Immunopharmacol | 6 | 1.23 | 4.7 | Q2 |
IF, impact factor.
Table 4. Co-citation literature of journals.
| Rank | Cited journal | Co-citation | IF [2024] | Quartile in category |
|---|---|---|---|---|
| 1 | Cancer Res | 301 | 16.6 | Q1 |
| 2 | Clin Cancer Res | 235 | 10.2 | Q1 |
| 3 | Cell | 228 | 42.5 | Q1 |
| 4 | Nature | 211 | 48.5 | Q1 |
| 5 | CA Cancer J Clin | 208 | 232.5 | Q1 |
| 6 | Nat Commun | 187 | 15.7 | Q1 |
| 7 | Int J Cancer | 186 | 4.7 | Q1 |
| 8 | PLoS One | 181 | 2.6 | Q2 |
| 9 | Front Immunol | 178 | 5.9 | Q1 |
| 10 | Nat Rev Cancer | 176 | 66.8 | Q1 |
IF, impact factor.
Figure 5.
Journal source analysis. (A) Density visualization of journal publication output. (B) Journal co-citation network map. (C) Dual-map overlay of journals.
The thematic distribution of academic publications was visualized using a dual-map overlay (Figure 5C). Colored paths represent citation relationships, with citing journals on the left and cited journals on the right. Two dominant citation trajectories were identified: studies published in molecular/biology/genetics journals were primarily cited by journals in the medicine/medical/clinical and molecular/biology/immunology domains.
Authors
Among all authors who have published studies on macrophages in esophageal cancer, Table 5 lists the top 10 most productive authors. Collectively, these authors published 136 papers, accounting for 27.98% of all publications in this field. Mari Nishio contributed the highest number of papers (n=20), followed by Manabu Shigeoka (n=20), Hiroshi Yokozaki (n=20), and Yu-ichiro Koma (n=17). CiteSpace was used to visualize the collaboration network among authors (Figure 6A).
Table 5. Author’s publications and co-citation rank literature.
| Rank | Author | Count | Co-cited author | Citation |
|---|---|---|---|---|
| 1 | Nishio M | 20 | Sung H | 96 |
| 2 | Shigeoka M | 20 | Mantovani A | 92 |
| 3 | Yokozaki H | 20 | Yang H | 61 |
| 4 | Koma Y | 17 | Shigeoka M | 58 |
| 5 | Kakeji Y | 12 | Bray F | 54 |
| 6 | Li F | 12 | Zheng YX | 53 |
| 7 | Kodama T | 11 | Abnet CC | 43 |
| 8 | Urakawa N | 8 | Kato K | 41 |
| 9 | Wang Y | 8 | Hanahan D | 39 |
| 10 | Yang L | 8 | Newman A | 39 |
Figure 6.
Author cooperation analysis. (A) Cooperation network of authors. (B) Co-citation network of authors.
Figure 6B and Table 5 present the top 10 authors ranked by co-citation frequency and total citations, respectively. In total, 20 authors were cited more than 30 times, indicating strong academic visibility and influence. The largest nodes corresponded to the most frequently co-cited authors, including Sung H (96 co-citations), Mantovani A (92 co-citations), and Yang H (61 co-citations).
Citation and co-citation analysis
Using a 1-year time slice over the period 2000–2025, the co-cited reference network comprised 2,429 nodes and 11,135 links (Figure 7A). Based on the top 10 most frequently co-cited articles (Table 6), the most highly co-cited publication was “Immune suppressive landscape in the human esophageal squamous cell carcinoma microenvironment” published in Nature Communications. This study delineated a detailed immune-cell atlas of ESCC and demonstrated that the crosstalk between macrophages and regulatory T cells (Tregs) contributes to an immunosuppressive microenvironment. The second-ranked article was the phase 3 randomized, placebo-controlled Lancet trial, “Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590)”, led by Sun JM, which supported the clinical benefit of immunotherapy in advanced esophageal cancer.
Figure 7.
Cited and co-cited reference analysis. (A) Network map of co-cited publications. (B) Cluster analysis of the co-citation network. (C) Peak-time visualization of co-cited literature. (D) Citation burst map of the referenced literature.
Table 6. Co-citation table of literature.
| Rank | Title | Journal | Author | Total citations |
|---|---|---|---|---|
| 1 | Immune suppressive landscape in the human esophageal squamous cell carcinoma microenvironment | Nat Commun | Zheng YX | 52 |
| 2 | Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study | Lancet | Sun JM | 32 |
| 3 | Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer | J Clin Oncol | Kojima T | 29 |
| 4 | Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial | Lancet Oncol | Kato K | 28 |
| 5 | Sprain energy consequences for damage localization and fracture mechanics | Mol Cancer | Yang H | 27 |
| 6 | Dissecting esophageal squamous-cell carcinoma ecosystem by single-cell transcriptomic analysis | Nat Commun | Zhang X | 26 |
| 7 | Tumor associated macrophage expressing CD204 is associated with tumor aggressiveness of esophageal squamous cell carcinoma | Cancer Sci | Shigeoka M | 19 |
| 8 | Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma | Cancer Sci | Baba Y | 19 |
| 9 | Tumour-associated macrophages are associated with poor prognosis and programmed death ligand 1 expression in oesophageal cancer | Eur J Cancer | Yagi T | 19 |
| 10 | Integrated single-cell transcriptome analysis reveals heterogeneity of esophageal squamous cell carcinoma microenvironment | Nat Commun | Dinh HQ | 19 |
We performed co-cited reference clustering and timeline analyses (Figure 7B,7C). The results indicated that esophagus (Cluster #5), nitric oxide (Cluster #6), cDNA array (Cluster #9), systems biology (Cluster #11), adjuvant chemotherapy (Cluster #16), and innate cellular immunity (Cluster #17) represented major early-stage research hotspots. NK cell (Cluster #7), CD204 (Cluster #8), muscularis propria (Cluster #10), Ilex paraguariensis (Cluster #12), glioma (Cluster #13), CXCR2 (Cluster #14), and esophageal repair (Cluster #15) emerged as mid-stage hotspots. More recently, immune signature (Cluster #0), single-cell RNA sequencing (Cluster #0), direct co-culture (Cluster #2), Kazakh (Cluster #3), and immunotherapy (Cluster #4) have become prominent themes and represent the current hotspots and evolving trends in this field.
Using CiteSpace, we identified the 50 most robust reference citation bursts in research on macrophages in esophageal cancer. All 50 references were published between 2000 and 2025, indicating that these studies have been repeatedly cited over the past nearly three decades. Notably, 20 of these references are currently in an active burst period (Figure 7D), suggesting that macrophage-related research in esophageal cancer will likely remain a sustained focus in the coming years.
Keywords and hotspots
By analyzing keywords, we can rapidly capture the research landscape and emerging directions in a field. In VOSviewer, the most frequent keyword was “esophageal cancer” (117 occurrences), followed by “tumor-associated macrophages” (88 occurrences), “prognosis” (81 occurrences), “tumor microenvironment” (63 occurrences), and “survival” (61 occurrences) (Table 7; Figure 8A,8B). After removing irrelevant terms, we built a co-occurrence network of 152 keywords (≥5 occurrences), which formed seven clusters. Overall, these clusters largely reflected themes related to immunotherapy and clinical outcomes, macrophage phenotypes and tumor progression, omics and modeling, and tumor microenvironment/inflammatory signaling, as well as topics such as biomarkers/signatures, exosomes/autophagy, and other immune/stromal components. Using CiteSpace, a volcano plot was generated to visualize temporal shifts in hotspots (Figure 8C,8D), indicating that TAMs, cytokines, immunotherapy, overall survival, and TCGA-based analyses remain prominent topics. Among the 676 burst keywords detected, we further extracted the top 50 strongest bursts (Figure 9), which represent current hotspots and potential future research directions.
Table 7. High frequency keyword table.
| Rank | Keyword | Counts |
|---|---|---|
| 1 | Esophageal cancer | 117 |
| 2 | Tumor-associated macrophages | 88 |
| 3 | Prognosis | 81 |
| 4 | Tumor microenvironment | 63 |
| 5 | Survival | 61 |
| 6 | Immunotherapy | 56 |
| 7 | Progression | 53 |
| 8 | Activation | 36 |
| 9 | Invasion | 36 |
| 10 | Growth | 33 |
| 11 | Chemotherapy | 32 |
| 12 | Inflammation | 30 |
| 13 | Poor-prognosis | 27 |
| 14 | Apoptosis | 23 |
| 15 | Migration | 23 |
| 16 | Biomarker | 22 |
| 17 | Therapy | 21 |
| 18 | Infiltration | 20 |
| 19 | Promotes | 20 |
| 20 | Regulatory t-cells | 20 |
Figure 8.
Analysis of keywords associated with macrophage-related research in esophageal cancer. (A) Network map of high-frequency keywords. (B) Density map of keywords. (C) Peak map of keyword clustering. (D) Clustering map of keywords.
Figure 9.
Bursting map of keywords.
Discussion
This bibliometric analysis provides a structured overview of macrophage-related research in esophageal cancer over the past 25 years. The steady expansion of publications suggests that macrophages have moved from a supportive topic within tumor biology to a central theme closely linked to immunotherapy, multi-omics profiling, and biomarker development. Beyond documenting growth, our co-citation and keyword-based maps clarify how the field’s intellectual base formed and how its current research fronts are being shaped.
A recurring mechanistic theme is macrophage plasticity (18,19). In esophageal cancer, TAMs are often discussed using M1/M2 terminology and commonly measured through markers such as CD163 or CD206, which broadly reflect immunoregulatory, tissue-repair-skewed states rather than discrete lineages (20,21). Functionally, these macrophage programs can sustain immune escape by reducing effective antigen presentation, producing suppressive cytokines [notably interleukin-10 (IL-10) and transforming growth factor-β (TGF-β)], and promoting regulatory immune networks (22). Importantly, treating “M2” as a single biological entity is increasingly insufficient: macrophage states can be simultaneously inflammatory and suppressive, and they can transition over time under therapy pressure (23). This heterogeneity likely explains why single-marker studies often show variable prognostic performance across cohorts and why more recent research has moved toward multi-feature immune signatures and transcriptomic state definitions.
The appearance of chemokine- and receptor-related terms in the mid-stage clusters (notably CXCR2) points to a second mechanistic axis: myeloid recruitment and spatial organization. While chemokine networks are often treated descriptively in earlier literature, the field’s thematic shift implies increasing interest in how recruitment/retention gates the establishment of suppressive niches (24). In esophageal cancer, TAM accumulation can reshape immune-cell trafficking and cytokine gradients, creating conditions that favor regulatory and exhausted phenotypes (25,26). This is mechanistically compatible with the strong linkage observed between macrophage-related keywords and clinical endpoints, and it also fits with why immunotherapy-focused literature becomes intertwined with macrophage biology: a myeloid-dominant microenvironment can limit the ceiling of response to programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade even when tumor-reactive T cells are present (27).
The co-citation prominence of immune-microenvironment mapping studies that emphasize macrophage-Treg crosstalk highlights a particularly plausible suppressive circuit. TAMs can support Treg recruitment and stability through chemotactic and cytokine-mediated mechanisms, while Tregs can reinforce suppressive macrophage programs, jointly constraining cytotoxic function (28,29). This reciprocal regulation offers a mechanistic bridge between the “immune suppressive landscape” knowledge base and the newer immunotherapy/frontline trial knowledge base represented in the co-citation network. In practical terms, it argues that resistance to checkpoint blockade in a subset of esophageal cancers may be “myeloid-organized” rather than purely T-cell intrinsic-an interpretation that is consistent with the increasing co-occurrence of immunotherapy agents alongside TAM and microenvironment terms in the keyword clusters (30).
The keyword cluster emphasizing angiogenesis, invasion, and matrix-related terms further suggests that TAM biology in this field is not only about immune suppression, but also about stromal remodeling that couples tumor aggressiveness with immune exclusion (31,32). TAM-derived pro-angiogenic mediators and matrix remodeling can facilitate invasion while altering perfusion, hypoxia, and immune-cell access—features that can indirectly modulate immunotherapy sensitivity and may explain why survival/prognosis remains tightly embedded in the keyword core. Importantly, this line of work connects older “inflammation mediator” themes to current “microenvironment systems” themes: once vascular and matrix remodeling are considered, macrophages become central to both structural and immunologic constraints on therapy (33).
Importantly, our results provide several insights for future research. First, future studies should move beyond the oversimplified M1/M2 framework and establish more refined and standardized TAM phenotyping systems in esophageal cancer, especially in the context of single-cell RNA sequencing, spatial transcriptomics, and multiplex imaging technologies. Second, more efforts are needed to integrate macrophage-related molecular features with clinicopathological parameters and treatment-response data, so as to develop robust prognostic and predictive models for patient stratification. Third, mechanistic studies should further dissect the functional interactions between macrophages and other cellular components in the tumor microenvironment, including tumor cells, T cells, fibroblasts, and myeloid-derived suppressor cells, in order to identify actionable signaling axes. Finally, these advances may support the development of macrophage-targeted therapeutic strategies, either alone or in combination with immune checkpoint inhibitors, thereby improving translational relevance in esophageal cancer management.
Strengths and limitations
A major strength of this study is the integrated use of complementary bibliometric platforms to characterize productivity, collaboration networks, co-citation structure, thematic clustering, and burst dynamics, providing a multidimensional view of the field and its evolution. The inclusion of cited references enables identification of the intellectual base and emerging fronts beyond simple publication counts. Limitations include restriction to WoSCC-indexed records and predominantly English-language coverage, which may omit relevant regional literature. Citation-based indicators are time-dependent and may disadvantage recent studies. Network topology and clustering results are also sensitive to parameter settings and database updates.
Conclusions
Overall, our bibliometric mapping does more than summarize productivity; it provides an interpretable scaffold for mechanism-driven research planning. The field’s intellectual base and current hotspots converge on a shared question: which macrophage programs and interactions are causal drivers of immune escape and outcome in esophageal cancer, and which of these are most tractable for combination strategies with checkpoint inhibitors. By aligning emerging methods with the biological mechanisms suggested by the knowledge clusters, future work can move toward biomarker-guided, macrophage-informed approaches that are both mechanistically grounded and clinically testable.
Supplementary
The article’s supplementary files as
Acknowledgments
We appreciate the data availability that was present via the Web of Science Core Collection, as well as the cooperation of all authors.
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.
Footnotes
Reporting Checklist: The authors have completed the BIBLIO reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2781/rc
Funding: None.
Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2781/coif). The authors have no conflicts of interest to declare.
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