A two-decade bibliometric analysis of tumor-associated macrophages in colorectal cancer research

ABSTRACT

Tumor-associated macrophages (TAMs), the predominant immune cells in the tumor microenvironment (TME), facilitate proliferation, invasion, metastasis, angiogenesis, chemoresistance, and immunosuppression in colorectal cancer (CRC). The mutual pathological mechanisms remain unclear, necessitating an in-depth study of the relationship between TAMs and CRC. This paper employs bibliometric methods to analyze TAMs and CRC research literature, aiming to assess current trends, evaluate the research status, and forecast future directions and emerging topics. We searched for publications published in the Web of Science Core Collection (WOSCC) database from January 1, 2001 to July 31, 2024. Following the establishment of specific search criteria for time, publication type, and language, bibliometric analysis and data visualization were conducted using Microsoft Excel, R software, VOSviewer, and CiteSpace. A total of 1,218 publications authored by 8,302 researchers across 61 countries and 1,657 institutions were analyzed. They were published in 427 journals, covering 4,451 keywords and citing 65,174 references. Keyword co-occurrence and literature co-citation analysis identified nuclear factor kappa-B, endothelial growth factor, angiogenesis, polarization, TME, immune response, programmed cell death protein 1 blockade, and metabolism as current research hotspots and trends in this field. Immune therapy and cancer-associated fibroblasts are key research areas, with the potential for further exploration of their mechanisms and targeted therapies. This paper employs bibliometric methods to comprehensively analyze and visualize research papers in TAMs and CRC. It analyzes the TAM-targeting research landscape in CRC, mapping current frontiers and translational potential to position TAMs as a promising immunotherapeutic strategy.

Introduction

Colorectal Cancer (CRC) is the 3rd most common cancer and 2nd leading cause of cancer deaths globally, with approximately 1,926,000 new cases and 904,000 deaths from CRC worldwide in 2022, representing a significant disease burden.¹ However, its etiology and pathogenesis have not been fully clarified. Advancements in diagnostic techniques, such as early CRC screening, circulating tumor DNA analysis, and gut microbiome analysis,^2,3 along with enhanced treatment options like neoadjuvant chemotherapy, molecularly targeted therapy, and immunotherapy, have improved prognosis and increased life expectancy for CRC patients.⁴ When CRC is definitively diagnosed, more than 50% of patients are in intermediate or advanced stages, lack effective treatments, and have poor prognoses. The median overall survival (OS) for metastatic colorectal cancer (mCRC) patients is 32–40 months, with only approximately 15.6% of those who cannot undergo surgical resection expected to achieve a 5-year OS.³ Meanwhile, the aging population and lifestyle changes leading to earlier onset of CRC will sustain high morbidity and mortality rates, resulting in a significant disease burden. It is, therefore, imperative to investigate the pathogenesis of CRC further and identify novel treatment modalities that will enhance its clinical efficacy on an ongoing basis.

Recent tumor research has shifted from a focus on cancer cells alone to a broader study of their interactions with the microenvironment and external factors. Tumor cells manipulate non-cancerous host cells and alter the vascular system and extracellular matrix (ECM) to create a supportive tumor microenvironment (TME) for their growth and development. TME is a structured ecosystem comprising diverse immune cells, cancer-associated fibroblasts (CAFs), endothelial cells, and ECM, among other components.⁵ TME is crucial in tumor progression, making it a novel target for interventional therapy.⁶ Tumor-associated macrophages (TAMs), the main immune cells in the TME, exhibit significant plasticity and heterogeneity, and cytokines, chemokines, and exosomes can activate them from the initial M0 state to either the classically activated M1 state or the alternatively activated M2 state.^7,8 M1 TAMs can be induced by T helper cell type 1 (Th1) factors, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-12, interferon-gamma (IFN-γ), lipopolysaccharide (LPS), and granulocyte-monocyte colony-stimulating factor (GM-CSF).⁹ Simultaneously, M1 TAMs exert pro-inflammatory and immune-enhancing actions, as well as anti-tumor effects. They accomplish this by secreting inflammatory cytokines such as TNF-α, IL-6, IL-12, and IL-23, producing reactive oxygen species to eliminate pathogens, and participating in antibody-dependent cell-mediated cytotoxicity (ADCC) to target and destroy tumor cells.^10,11 M2 TAMs can be activated by anti-inflammatory factors like transforming growth factor-beta (TGF-β), macrophage colony-stimulating factor (M-CSF), IL-4, IL-10, IL-13, and immune complexes, leading to high expression of CD206, CD163, and arginase-1 (Arg-1).^9,12 M2-type TAMs depend on high levels of oxidative phosphorylation and also produce anti-inflammatory cytokines, which exert anti-inflammatory, tissue repair, wound healing, angiogenesis, immunosuppression, and tumor cell growth and metastasis-promoting effects.¹³ TAMs in tumors mostly show dynamic and continuous changes, and the M1 type in the early stage of the tumor is often adapted and polarized to the M2 phenotype by tumor cells with tumor progression to play a pro-cancer role and form a vicious circle.¹⁴ During tumor progression, transitional non-M1 or M2 phenotypes significantly contribute to tumor cell proliferation, invasion, metastasis, and other cancer-promoting processes, correlating with poor patient outcomes.¹⁵ TAMs have been demonstrated to be intimately linked with CRC, and they can promote CRC proliferation, invasion, metastasis, angiogenesis, chemotherapy resistance, and immunosuppression.^16,17 For example, CRC cell-derived exosomal microRNA (miR)-934 promotes M2 TAM polarization by down-regulating phosphatase and tensin homolog (PTEN) expression, activating the activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, and secreting C-X-C motif Chemokine Ligand 13 (CXCL13), which facilitates pre-metastatic niche formation and CRC liver metastasis.¹⁸ In CRC, the immunogenic molecule CD155 is overexpressed in cancer cells and is associated with poorer survival rates among CRC patients. Furthermore, TAMs expressing CD155 contribute to the M2 phenotypic shift, suppression of immune responses, and the advancement of tumor growth in CRC.¹⁹ CRC-derived miR-21-5p and miR-200a synergistically regulate the PTEN/AKT and suppressor of cytokine signaling 1 (SCOS1)/signal transducer and activator of transcription 1 (STAT1) pathways, inducing M2 TAM polarization and programmed cell death-Ligand 1 (PD-L1) expression, thereby diminishing CD8⁺ T cell activity and promoting tumor growth.²⁰ Runt-related transcription factor 1 (RUNX1) recruits macrophages and induces polarization of M2-type TAMs in CRC through the production of C-C motif ligand 2 (CCL2) and activation of the Hedgehog pathway and TAMs-related platelet-derived growth factor (PDGF)-BB both fosters CRC tumor angiogenesis and boosts RUNX1 expression in CRC cell lines, promoting CRC migration and invasion in vitro.²¹

CRC is closely related to TAMs, and their interactions have been widely studied, such as a review discussing the mechanism of action that TAMs can promote CRC occurrence, invasion, metastasis, angiogenesis, immunosuppression, etc., but the key point is the therapeutic effect of natural compounds on them.²² Currently, most reviews of TAMs and CRC focus on a specific drug, a specific pathway or mechanism of action, and it is not clear how the focus of TAMs and CRC has changed longitudinally and what the current status of research in the field is, what the current hotspots are, and what the future trends will be. Therefore, it is necessary to choose a different research method from traditional reviews to explore the specific mechanism of action and therapeutic potential in this field. Bibliometrics, a multidisciplinary field that combines methodologies from mathematics, statistics, and library science, enables the quantitative and visual assessment of research landscapes, facilitating the identification of key research focal points and emerging trends.^23–25 At this stage, although there are bibliometric articles on TAMs, the research topics are broad or focused on the study of the relationship between the role of TAMs and other diseases, such as ulcerative colitis and atherosclerosis^24,26,27 and the focus of the research on TAMs in the specific disease of CRC have not yet been clarified, which restricts the direction of development of the research field of TAMs and CRC. Therefore, in view of the complex relationship between TAMs and the development of CRC, this paper intends to utilize bibliometric methods to explore the current development of TAMs in CRC research, to identify research hotspots and to predict future development trends by analyzing the years of publications, the numbers, the countries, the institutions, the authors, the disciplines, the citations and the keywords of publications in this field. In order to focus on exploring the molecular signaling pathways or mechanisms of action through which TAMs act on CRC, and to provide directions for the in-depth analysis of the mechanisms in this field and the clinical translation of targeting TAMs for the treatment of CRC. Meanwhile, TAMs is a popular immune cell in CRC research in recent years, and this paper can further clarify the changing pulse of its role pathways and concerns in the immune microenvironment of CRC, and can also point out the future direction of research and provide reference for researchers in the field of CRC and TAMs in a timely manner.

Methods

Retrieval strategy

This paper utilized the Web of Science Core Collection (WOSCC) database as its data source. Only WOSCC was used in this article, which does have limitations and does not fully reflect the current state of research in the field. We used three bibliometric tools to analyze the data, and the data exported by WOSCC was fully supported. However, the data exported by Scopus, PubMed, or Google Scholar have certain limitations for these tools and cannot support them simultaneously for in-depth analysis. Therefore, we chose to apply only the WOSCC database. To ensure the accuracy of the results and data, we optimized the search method based on previous papers^25,28 and used “tumor-associated macrophages” and “colorectal cancer” as the designated search terms. In addition, synonyms or related terms (e.g., “CRC” OR “LARC” OR “LACC”) were used for search terms. Comprehensive search algorithms are detailed in the Supplementary Material. The publication date was set from January 1, 2001 to July 31, 2024. The article was written in English and classified as either an Article or a Review Article. To prevent systematic bias from database updates, we completed publication retrieval completed on August 9, 2024.

Data collection and processing

The extracted information covers the title, abstract, country, institution, author, journal, year of publication, references, and keywords of the publication. The scholarly H-index and Journal Citation Report (JCR) were derived from WOS, and the impact factor (IF) was obtained from the journal’s official website. For duplicate records, we used CiteSpace to remove duplicate values. In addition, we read the titles and abstracts of the included literature and handled missing values by manual proofreading to ensure compliance. We cleaned the data from duplicate items, double-proofread, merged, and exported them for further analysis. To minimize bias, we referred to a large body of literature on bibliometrics and organized it according to their experience. Corresponding authors would be consulted in case of unresolved conflicts during the quality assessment process.

Data analysis

In this paper, Figdraw (www.figdraw.com) was used to create the flowchart. Statistical tables and trend graphs were generated using Microsoft Excel 2021. Lotka’s Law analysis and heat maps were produced using the Bibliometrix 4.3.0 package in R version 4.4.1. For bibliometric analysis of countries, institutions, authors, journals, references, and keywords, we used VOSviewer 1.6.20 and CiteSpace 6.3 R1. Each software was selected based on its capability to support different types of analysis and visualization, enabling us to present results from multiple analytical perspectives. The final outputs focused primarily on co-authorship, co-occurrence, and co-citation analyses.

Results

As of August 9, 2024, 1,277 publications were retrieved from WOSCC. Based on the exclusion criteria related to publication time, article type, and language, 59 papers were excluded. Finally, 1,218 papers (document types: 897 Articles and 321 Review Articles) were screened for the bibliometric analysis of TAMs and CRC articles. The specific flow chart is shown in Figure 1.

Figure 1.

Flow diagram of the search strategy and eligibility criteria.

Trends in global growth in the publication volume

Supplementary Figure S1 depicts the publication trends for TAMs and CRC papers. The figure illustrates a general upward trend in articles published from 2001 to 2023. Prior to 2010, annual publications were fewer than 20. From 2011 to 2016, there was steady growth in the number of publications, totaling 216 articles, or approximately 17.7% of the overall publications. Between 2017 and 2023, the number of published articles increased significantly, comprising approximately 66.3% of the total publications. 2022 and 2023 had more than 150 articles published, and 2024 already had more than 100 articles published. Although we only analyzed article counts for seven months in 2024, preliminary predictions suggest that the total number of articles for the year will surpass 2023, potentially reaching the highest position. This indicates that the fields of TAMs and CRC have received increasing attention and have become popular research directions.

Distribution of countries

A total of 61 countries have published in the field of TAMs and CRC, and Supplementary Table S1 shows the top 10 countries by publication count. Among them, China (N = 555) produced the most publications, followed by the United States of America (USA) (N = 244) and Japan (N = 109). Also, China (N = 19,445) was the most cited country, followed by the USA (N = 15,032) and Italy (N = 11,801). Despite having the highest number of publications, China’s average article citations (N = 36.40) surpass only Poland (N = 19.50) in the table and fall significantly below Italy (N = 178.80), France (N = 112.40), Germany (N = 111.40), USA (N = 92.80), Sweden (N = 88.70), and the United Kingdom (N = 87.00). This indicates that the publications of Chinese researchers are still insufficient in terms of academic impact in the field of TAMs and CRC, and they urgently need to carry out more in-depth research work and publish higher-level academic papers in order to enhance their influence in the international scholarly community. In addition, the annual publication volume in most countries peaks in 2021–2023 (Supplementary Figure S2A).

Supplementary Figure S2B is a network diagram of state cooperation, reflecting the linkages and cooperation between states. Supplementary Table S1’s node centrality size indicates the closeness of cooperation between countries, with larger centrality signifying a higher degree of association. China’s centrality score of 0.39 signifies its close cooperation with international publications and its pivotal role in this research field. The USA (N = 0.31), Germany (N = 0.24), United Kingdom (N = 0.24), and Italy (N = 0.22) are key nodes in the cluster, indicating significant collaboration. Although Japan also has a high number of publications, it has a low centrality, indicating that it collaborates less with other countries. South Korea and Poland have a centrality of 0, implying that these two countries have no cooperation with other countries.

Distribution of institutions

The publications of TAMs and CRC involve 1,657 institutions and Supplementary Table S2 shows the top 10 most productive institutions. Among them, Sun Yat Sen University tops the list with 52 published articles, significantly more than other institutions. Nine of the top 10 institutions are located in China, indicating that Chinese institutions have high research enthusiasm in TAMs and CRC and have achieved some research results. However, the centrality of most institutions is low, and only the Chinese Academy of Sciences exceeds 0.1, which indicates that the degree of cooperation among most Chinese institutions is relatively low. Although only Harvard University among the top 10 institutions does not belong to China, it has the highest centrality degree, which suggests that it has more cooperative exchanges with institutions in other countries. Supplementary Figure S3 illustrates the main clusters of the composition of issuing institutions. The sparse connectivity among institutions indicates a need for enhanced cooperation and communication to facilitate experience sharing and mutual reference, ultimately leading to the publication of higher-quality articles.

Analysis of authors and coauthors

The study on TAMs with CRC involved 8,302 authors. Supplementary Figure S4A illustrates the author’s productivity in accordance with Lotka’s law. As shown in the figure, 82.7% of authors in the TAMs and CRC research area have published 1 paper, 10.6% of authors have published 2 papers, and only 3.70% have published 3 papers. Supplementary Table S3 presents the publication count and frequently co-cited authors in the TAMs and CRC research domain. Mantovani, Alberto (N = 17, H-index = 189) from Humanitas University had the most publications, followed by Xiong, Bin (N = 51, H-index = 35) from Wuhan University and Marchesi, Federica (N = 9, H-index = 32) from University of Milan. Meanwhile, the top 3 cited authors were Mantovani, Alberto (N = 518, H-index = 189), Antonio Sica (N = 219, H-index = 76), and Qian, Binzhi (N = 190, H-index = 51). The above authors have contributed their significant efforts in the research of TAMs and CRC and laid the foundation for the development of the field. Meanwhile, we found that except for Mantovani, Alberto, the rest of the highly cited authors do not appear in the table of highly productive authors. The H-index of the highly cited authors is higher than the highly productive authors as a whole, which indicates that the highly cited authors have published fewer articles but have a high academic impact and have gained a higher number of citations through a smaller number of publications. In addition, we constructed an author collaboration network graph (Supplementary Figure S4B), in which the two main clusters are the green cluster (dominated by Chinese scholars) and the red cluster (dominated by foreign scholars), indicating the existence of a positive collaborative relationship between authors in the clusters. Linked nodes in different clusters exhibit a degree of collaboration, such as Pinto, Marta L. (blue cluster) and Barbosa, Mario A. (blue cluster) and Mantovani, Alberto (red cluster), Oliveira, Maria J. (blue cluster) and Donadon, Matteo (red cluster).

Journal and citation analysis

A total of 427 journals are involved in the study of TAMs with CRC. Supplementary Table S4 lists the top 10 journals in the TAMs and CRC field based on publication count and citation frequency. The journal with the highest number of publications was Cancers (N = 46), followed by Frontiers In Immunology (N = 42) and International Journal Of Molecular Sciences (N = 38). Of the top 10 journals by publication volume, 8 are classified as Q1 in the JCR, and 1 as Q2. Additionally, 4 journals have an IF above 5, with Cancer Research and Molecular Cancer exceeding an IF of 10. Cancer Research leads the top 10 cited journals with 951 citations, followed by Clinical Cancer Research with 789 citations and Nature with 776 citations. Eight journals were classified as Q1 in the JCR partition, and two as Q2. Additionally, eight journals had an impact factor exceeding 5, including top-tier journals such as Nature, Cancer Cell, and Nature Reviews Cancer. Meanwhile, most journals are growing rapidly, with their annual publication volume peaking in 2021–2023 (Supplementary Figure S5A). While PLoS One, Oncoimmunology, Anticancer Research, Molecular Cancer, and Cancer Research were involved in TAMs and CRC earlier, their publication volume peaked in 2014–2019. Supplementary Figure S5B shows the journal network diagram, which reflects the degree of collaborative exchange between journals. The graph is segmented into six clusters. Node size indicates the number of published articles, line thickness denotes the strength of associations, and similarly colored journals share related topics.

Analysis of research disciplines

Supplementary Figure S6 presents a double graphical overlay of journals in the TAMs and CRC fields, revealing the evolution of the discipline’s development. The sizing journals on the left represent the frontier areas of knowledge, whereas the cited journals on the right denote the discipline’s knowledge base. The connecting line between the two parts illustrates the disciplinary relationship between the citing and cited journals. The thickness of the connecting lines reflects the strength of the linkage, while the z-Scores function labeled on the main connecting lines highlights the strength of the linkage, the smoothness of the trajectory, and the score.

As can be seen from Supplementary Figure S6, the citing journals are mainly related to discipline #2 (MEDICINE, MEDICAL, CLINICAL) and discipline #4 (MOLECULAR, BIOLOGY, IMMUNOLOGY); the cited journals are primarily associated with discipline #5 (HEALTH, NURSING, MEDICINE) and discipline #8 (MOLECULAR, BIOLOGY, GENETICS). The yellow path (z = 6.35, f = 26,692) and the green path (z = 2.24, f = 10,126) indicate that publications in the disciplines of molecular, biology, immunology and medicine, medical, and clinical disciplines, respectively, are significantly influenced by publications in the disciplines of molecular, biology, genetics disciplines’ publications.

Analysis of references co-citation, clustering, timeline, and bursts

Table 1 lists the 10 most highly cited articles in TAMs and CRC research, with the article entitled Cancer-related inflammation (N = 8,468) by Mantovani, Alberto being the most cited. This article points out that mediators and cellular effectors of inflammation are essential components of the TME and that TAMs in the TME significantly impact tumor cell development and progression.²⁹ This paper represents a significant advancement in TAM research, establishing a robust foundation for future investigations into TAMs and CRC.

Table 1.

Top 10 most cited literature in TAMs and CRC research.

Rank	Title	DOI	First Author	Year	Journal	Citations (as of August 9, 2024)	Average per Year
1	Cancer-related inflammation	10.1038/nature07205.	Mantovani, Alberto	2008	NATURE	8,468	529.25
2	Inflammation and Cancer: Triggers, Mechanisms, and Consequences	10.1016/j.immuni.2019.06.025.	Greten, Florian R.	2019	IMMUNITY	1,966	393.20
3	PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity	10.1038/nature22396.	Gordon, Sydney R.	2017	NATURE	1,424	203.43
4	Roles of the immune system in cancer: from tumor initiation to metastatic progression	10.1101/gad.314617.118.	Gonzalez, Hugo	2018	GENES & DEVELOPMENT	1,204	200.67
5	Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis	10.1038/nrgastro.2017.119.	Jia, Wei	2018	NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY	1,049	174.83
6	Immunotherapy in colorectal cancer: rationale, challenges and potential	10.1038/s41575-019-0126-x.	Ganesh, Karuna	2019	NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY	995	199.00
7	The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy	10.1038/s41568-020-0285-7.	Bruni, Daniela	2020	NATURE REVIEWS CANCER	838	209.50
8	Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted Therapies in Colon Cancer	10.1016/j.cell.2020.03.048.	Zhang, Lei	2020	CELL	703	175.75
9	Prognostic Significance of Tumor-Associated Macrophages in Solid Tumor: A Meta-Analysis of the Literature	10.1371/journal.pone.0050946.	Zhang, Qiong-wen	2012	PLOS ONE	676	56.33
10	Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy	10.1186/s40425-017-0257-y.	Cannarile, Michael A.	2017	JOURNAL FOR IMMUNOTHERAPY OF CANCER	662	94.57

Table 1 lists the 10 most highly cited publications in the field of TAMs and CRC and shows their links, years, and journals.

Supplementary Figure S7A shows the results of the literature co-citation analysis, which reveals the progress of TAMs and CRC research. Larger nodes indicate that the literature is cited more frequently. We labeled several key nodes with earlier years but not shown due to lower citation frequency to better demonstrate the overall trend of literature co-citation for TAMs and CRC papers. From this, most of the highly cited literature appeared between 2010 and 2021 and is particularly prominent between 2017 and 2021, suggesting that research in TAMs and CRC has progressed rapidly during this period.

Supplementary Figure S7B shows the literature co-citation clustering map for TAMs and CRC research, reflecting the research focus in this area. The figure identifies 16 clusters, highlighting “#0 tumor microenvironment,” “#2 m2,” and “#3 colorectal cancer” as key research hotspots in TAMs and CRC.

Supplementary Figure S7C presents a timeline of literature co-citation clustering, illustrating the evolving research trends in TAMs and CRC. The node and label colors in the figure show a gradual change from left to right over time. The nodes on the left side are mostly early and well-studied topics, while the nodes on the right side are mostly emerging topics in recent years. Early papers mainly centered on “#13 nonsteroidal anti-inflammatory drugs” and “#12 MCP-1” (monocyte chemotactic protein-1), which mainly investigates the inflammatory response and mentions the concept of “#10 organ microenvironment.” In recent years, research has focused on “#3 colorectal cancer” and “#2 m2” macrophages, emphasizing the “tumor microenvironment.”

Supplementary Figure S7D presents a burst analysis of literature co-citations, facilitating the examination of the duration of prominent topics in TAMs and CRC. The green line in the figure indicates the time span from the article’s publication to the search’s completion, whereas the red line denotes the outbreak duration. Among them, the highest intensity of outbreaks was Mantovani A’s article “Tumor-associated macrophages as treatment targets in oncology” (2018–2022, strength 26.79) published in 2017, which proposed that macrophages are critical factors in promoting inflammation in tumors and that targeting TAMs is very promising for the treatment of tumors.³⁰ Moreover, in the second and third places of outbreak strength are “Tumor-associated macrophages: from mechanisms to therapy” (2016–2019, strength 19.36) published by Noy R and “Macrophage diversity enhances tumor progression and metastasis” (2011–2015, strength 17.78) published by Qian BZ, respectively.

Keyword co-occurrence, clustering, and burst analysis

A total of 4,451 keywords were extracted. Table 2 highlights the key molecules and pathological processes associated with TAMs and CRC. The most frequently mentioned molecular keywords are nuclear factor kappa-B (NF-κB) (N = 105), endothelial growth factor (N = 65), and TGF-β (N = 49). The most frequent pathological process keywords were progression (N = 217), angiogenesis (N = 187), and polarization (N = 176).

Table 2.

Top 10 molecules and pathological processes linked to TAMs and CRC research.

Rank	Molecules	Count	Pathological processes	Count
1	nf-κb	105	progression	217
2	endothelial growth factor	65	angiogenesis	187
3	tgf-β	49	polarization	176
4	chemokine	28	metastasis	166
5	necrosis-factor-α	24	inflammation	153
6	cytokines	17	activation	143
7	beta-catenin	14	growth	110
8	interferon-gamma	14	infiltration	82
9	tnf-α	14	epithelial-mesenchymal transition	80
10	colony-stimulating factor	13	proliferation	63

The keyword network (Figure 2a) reveals the distribution of topics in the TAMs and CRC research area and better reflects the mechanisms associated with this research area. There are 3 color clusters of keywords in the figure, the largest of which is the red cluster, which reflects the environment, immune cells, and molecular proteins that are associated with the presence of TAMs with CRC and the diseases that are associated with them, such as TME, NF-κB, TGF-β, endothelial growth factor, t-cells, dendritic cells, breast-cancer and lung-cancer. Meanwhile, the green cluster mainly reflects the pathological processes of tumor cells, such as progression, metastasis, growth, proliferation, and invasion. The blue cluster mainly investigates the processes related to TAMs and their relationship with tumor therapy, such as polarization, infiltration, activation, chemotherapy, and prognosis.

Figure 2.

Keyword co-occurrence, clustering, and burst analysis. (a) Keyword network diagram of TAMs and CRC research. (b) The top 50 keywords with the strongest citation bursts.

Figure 2b shows the keyword burst in TAMs and CRC research, which reflects the hot trend of keywords and their duration in a specific period. The keywords that exploded in the early period (2001–2010) were mainly endothelial growth factor, angiogenesis, bone marrow, growth factor, chemoattractant protein 1, and NF-κB. Among them, angiogenesis and bone marrow were very hotly researched, lasting from 2002 to 2017. By the midterm (2011–2018), the trend of keyword bursts weakened significantly, mostly involving research on cytokines and related pathways, such as stem cells, myeloid cells, STAT3, and PD-1 blockade. Most of the papers in recent years (2019–2024) are related to cancer immunotherapy, further expanding to immune checkpoint inhibitors, CAFs, and so on, based on preimmune response; the depth of TME and the relationship with metabolic reprogramming have become a hotspot and trend of research.

Discussion

Recruited and activated by tumor cells, mesenchymal stromal cells, cytokines, and chemokines in the TME, TAMs facilitate tumor progression by promoting angiogenesis, immunosuppression, and metabolic regulation. However, TAMs can also exhibit anti-tumor effects based on their activation status and the surrounding TME. The interaction and crosstalk linkage between TAMs and TME is a hot mechanism in current tumor research, and the related papers are particularly significant in CRC, a highly prevalent cancer, and TAMs have been shown to be an essential target for the treatment of CRC disease.³¹ In order to clarify the research status, research hotspots, and development trends in TAMs and CRC, WOSCC, an authoritative database with high-quality papers, was selected for bibliometric analysis. In terms of global publication output, the number and trend of papers related to TAMs and CRC are on the rise, and researchers emphasize the related field as a hot direction for current and future research.

The analysis revealed that many countries, represented by China, have provided a large amount of resources, such as research funds and personnel, to strongly support the research on TAMs and CRC, demonstrating the importance of this field. The total number of publications does not necessarily correlate with academic impact, as the highest total citations may result from a greater number of publications. In contrast, the mean citation count, which represents the academic impact, is lower. This reflects that the quality of papers is the first gold standard of research, not the number of papers. China also needs to continuously reform the paper evaluation system, crack down on low-level, low-quality papers and research teams with poor academic integrity, and encourage research to shift to high-level, high-quality, and top-of-the-industry, and publish high-level research papers instead of emphasizing the number of papers published, in order to continuously improve its academic influence and academic integrity ability in the world. In terms of the degree of close exchange between countries, China and USA node centrality is as high as 0.39 and 0.31, respectively, which is the country with the closest academic exchange with other countries. It can be seen that, except for China and the USA, other countries have fewer publications, which means that their representative research results are insufficient. This may be caused by the excessive gap in comprehensive strength between different countries, inadequate investment in research, uneven resources in higher education, less cultivation of the number of research talents, technological barriers in research, poorer innovation capacity, insufficient cooperation and exchanges between countries, and fewer publications in English due to language differences. The solution to this problem is to strengthen global cooperation and address issues such as geographical differences in research funding, cooperation, and innovation. First, we can promote academic exchanges and dissemination by increasing global academic sharing such as organizing international conferences and sharing the latest research results in this field on a regular basis; second, we need to promote cooperation in higher education, facilitate visits of scholars, student exchanges, and carry out educational cooperation programs between different countries to promote the cultivation of scientific research talents; third, we need to carry out transnational joint fund grant programs to encourage top scientists in the field from different countries to work together in a win-win manner Third, we should carry out transnational joint fund projects to encourage top scientists from different countries to work together to solve key technical problems; fourth, countries with close cooperation should play a leading role in international cooperation and exchanges, and jointly promote international exchanges and cooperation in the fields of TAMs and CRC to promote the continuous progress of research in the field; fifth, we should realize real-time data sharing and confirmation of results through new technologies such as artificial intelligence and big data on the Internet, so as to avoid the duplication of research and the wastage of resources. Promoting close academic exchanges between different countries will be conducive to producing research results, improving research quality, reaching research consensus, and promoting the research process.

The distribution trends of research institutions and countries in TAMs and CRC are generally consistent. In addition to paying more attention to the quality rather than the quantity of papers in order to improve the academic impact, China also needs to strengthen the cooperation between the internal institutions and can integrate the research funds and other resources based on the Chinese Academy of Sciences to create an academic research community, to avoid homogenization of the research content and low quality of different institutions, and to make the relevant personnel of the various institutions in China unite and work with each other, and to work together on TAMs and CRC. At the same time, it is also necessary to actively learn from the experience of cooperation and exchange with outstanding foreign institutions in order to overcome the problems in the field together.

The results of the authors’ and coauthors’ analysis revealed that Mantovani, Alberto, Xiong, Bin, and Marchesi, Federica are the leading researchers currently studying the relationship between the role of TAMs and CRC, and the three of them have the highest number of publications. Mantovani, Alberto, Antonio Sica, and Qian, Binzhi are the most cited researchers, and the three of them have the most substantial academic influence in this field. They have laid a solid foundation for subsequent scholars to conduct more in-depth research and led the way for the development of TAMs in CRC. In addition, the authors’ cooperation map shows that the researchers have formed a stable cooperation team. However, cooperation is mainly limited to the same country and institution, and authors from different countries and institutions should strengthen cooperation and communication to promote academic sharing and further progress.

The examination of scholarly publications concerning TAMs and CRCs reveals that eight out of the top ten journals featuring such research are classified within the JCR Q1 category. Most of them are open access (OA) journals, which aim to promote the sharing of academic knowledge, break down academic barriers by providing free and open access to articles globally and increasing the transparency of peer review, and do not excessively limit the number of articles to be published every year while meeting the quality requirements of the journals so that the number of published articles is relatively high. The above OA journals’ quality of the articles can be generally guaranteed, and the journals receive manuscripts with the theme of tumor, immunity, and other directions, which become the critical journals and the main force for publishing and publicizing the field of TAMs and CRC. The top 10 cited journals even include the prestigious international journal Nature. It is clear that the above two indicators are still a strong guarantee of the quality of papers, and the better the performance of the indicators, the better the reputation of the journal, the higher the quality of the research published in the journal, and the easier it is to be cited, thus generating a high level of academic impact. Therefore, researchers should strive to improve the quality of their research and publish in top journals with international reputations. Meanwhile, the annual publication volume of journals shows that 2021–2023 is an explosive period for research on TAMs and CRC, and it is predicted that the research trend in this field will continue further.

Journal discipline analysis provides a clear picture of the trends in the discipline. The fields of molecular, biology, genetics, and immunology seek to understand the molecular interactions between TAMs and CRC, as well as the mechanisms of immunosuppression and phenotypic transformation. This knowledge aims to advance medicine, medical and clinical practices by promoting the development of therapeutic drugs targeting TAMs for CRC treatment. At the same time, multidisciplinary cross-fertilization has become an inevitable trend in the development of medicine, and this field is no exception. In addition to basic molecular science, biology, genetics, immunology, and other disciplines, it is also necessary to continue to integrate with the frontier scientific and technological disciplines, such as artificial intelligence, big data, and so on, in order to promote subversive breakthroughs in research.

By analyzing the references of TAMs and CRC, it found that the top 10 most cited articles included 7 review articles, 2 basic experimental articles, and 1 meta-analysis, which mainly included the interaction between inflammation and tumor, the progress of CRC immunotherapy, TAMs and tumor immunity such as the phagocytosis of TAMs correlated with programmed cell death protein 1 (PD-1), and the innovative technologies like single-cell sequencing in TAMs and tumors. The most highly cited article elucidated how inflammation drives cancer progression by promoting processes such as cell proliferation, angiogenesis, immunosuppression, and metastasis, and revealed the central role of transcription factors such as NF-κB, STAT3, and other transcription factors in orchestrating the inflammatory response in the tumor microenvironment; however, it under-discussed the oncostatin effects of specific immune cells (e.g., M1-type macrophages), which may have weakened the complexity of inflammation in cancer.²⁹ The second most highly cited article revealed a high degree of cellular (e.g., macrophages, fibroblasts, neutrophils) plasticity in the TME, but the cancer suppression functions and mechanisms of certain inflammatory types (e.g., Th1-type immune response, M1-type macrophages) were more superficially analyzed.³² The third most highly cited article revealed a novel role for the PD-1/PD-L1 pathway in TAMs, but it relied heavily on the mouse CRC transplantation tumor model, which could not fully mimic the interaction of multiple immune cells in human TME.³³ Also, most of the highly cited literature was published in 2017–2021, which confirms that TAM and CRC research is getting deeper and deeper in that timeframe on the basis of the previous period and that researchers are combining novel technologies and many recently discovered mechanisms such as immune checkpoints with the field in order to enhance anti-tumor immunotherapeutic strategies. Co-citation analysis reveals that research on TAMs and CRC predominantly addresses TME, M2-type TAMs, and single-cell sequencing, indicating a deep exploration of these underlying mechanisms. In terms of the literature burst, in the early stage, we first confirmed the pro- and anti-cancer roles of macrophages and their potential therapeutic targets^34–36 and the inflammatory microenvironment of tumors.²⁹ In the middle stage, we gradually evolved into the phenotypic functions of TAMs, such as the roles of M1 or M2 in CRC,³⁷ and elaborated on the specific mechanisms of action and strategies for targeting TAMs to treat tumors.³¹ In the late stage, we focused more on the relationship between TAMs and immunotherapy.³⁸ For example, the presence of PD-1 on TAMs can inhibit phagocytic activity and weaken immune responses against tumors.³³

From the analysis of keyword co-occurrence and clustering, it is clear that research on TAMs and CRC mainly focuses on three parts. The first is the mechanism of TAMs regulating CRC progression, such as invasion, metastasis, angiogenesis, and immunosuppression; the second aspect pertains to the molecular biological underpinnings of the mechanisms at play during its functional process, such as NF-κB, TGF-β, endothelial growth factor, and chemokines; and the third is the exploration of clinical treatment of CRC by targeted TAMs such as potentiated chemotherapy and immunotherapy. This is related to the different stages of TAMs in CRC research and also corresponds to the different stages of research objectives in this field from the side. First, when TAMs are first identified in CRC, the basic role of TAMs in CRC is inevitably focused on, and the research goal is the phenotypic characteristics of TAMs and their specific mechanisms of regulating the progression of CRC, such as angiogenesis, immunosuppression, and so on. Furthermore, after the initial understanding of the pro-cancer or anti-cancer functions of TAMs phenotypes, the research goal will be to analyze the molecular biological basis of TAMs in the process of mechanism of TAMs, such as NF-κB, etc., to reveal the specific pathways of regulation. Finally, based on the above research, we will begin to explore the clinical application of targeting TAMs, with the goal of continuously demonstrating their value in clinical diagnosis and immunotherapy, such as combining with immunosuppressants such as PD-1, for clinical drug development and translational application.

The results of the keyword burst show that their research contents and research objectives are roughly the same as above, while the research direction, hot content, and duration of different stages can be clearly distinguished. In the early stage (2001–2010), the research objectives on TAMs and CRC focused on tumor progression mechanism, tumor prognosis, and in vivo experimental research explorations; endothelial growth factor, angiogenesis, TNF-α, and NF-κB had a higher intensity of outbreaks and were the focus of attention and longer duration of research in the field. Angiogenesis is a crucial pathway and independent prognostic factor for CRC progression,^39,40 with vascular endothelial growth factor (VEGF) acting as a key mediator that promotes neovascularization and increases vascular permeability, thereby facilitating CRC proliferation and metastasis. Papers have shown that TAMs increase the angiogenic process in CRC by releasing pro-angiogenic factors such as VEGF in tumor tissues, that TAMs correlate significantly with VEGF levels in cancer cells, and that TAMs infiltrated in tumors produce VEGF and release it into serum to increase circulating VEGF levels in CRC patients.⁴¹ TAMs can produce the pro-inflammatory cytokine TNF-α, which at low levels can induce epithelial-mesenchymal transition (EMT) and angiogenesis and promote metastasis in CRC cells.⁴² NF-κB contributes to CRC progression by engaging in EMT, angiogenesis, and the regulation of cancer stem cells. This activity stimulates the release of inflammatory cytokines like TNF-α, IL-6, and IL-1β, enhancing inflammation and CRC development. Additionally, it modulates TAM levels in the TME and decreases tumor cells’ responsiveness to chemo- and radiotherapy.⁴³ Early research in this field primarily focused on the mechanisms by which TAMs promote CRC progression, particularly in relation to angiogenesis and the transformation of inflammation into tumors.

In the mid-term (2011–2018), the research goal is to further shift to the development of clinical applications and therapeutic strategies on the basis of exploring the mechanism of action and molecular basis of TAMs and CRC in the early stage, especially focusing on the research of immunotherapy such as PD-1. This phase of research is mostly a continuation and deepening of the earlier research, including broadening to related receptors based on the early endothelial growth factor research, researching anti-angiogenic therapeutic strategies on the mechanism of action of angiogenesis, and further deepening the mechanism of action of inflammatory diseases and CRC such as bone mesenchymal stem cells can regulate inflammatory cells, especially macrophages, to prevent and treat inflammatory bowel disease-associated CRC.⁴⁴ The research also delves into the dynamic functions of various myeloid cells within the TME of CRC, including the intricate mechanisms of tumor promotion and inhibition. This encompasses the processes by which monocytes are drawn to and infiltrate tumor sites to differentiate into TAMs, as well as their impact on the immune system’s ability to mount anti-tumor responses through the modulation of lymphocyte activity. Notably, the immunotherapeutic role of TAMs in CRC has become the focus of much attention, involving keywords such as stem cells, immune response, PD-1 blockade, and STAT3, which profoundly reflects the change in research objectives. CRC originates from cancer stem cells, and research indicates that patients with higher stem cell scores have a worse prognosis. This is characterized by increased immunosuppressive components in the TME, such as macrophage M0 and M2 infiltration, reduced sensitivity to immunotherapy, and poorer responses to treatments like anti-PD-L1 and anti-PD-1; the specific mechanism for this may be the enrichment of the high stem cell score group for the IFN-γ response, IFN-α response, which is associated with the P53 pathway, KRAS signaling, EMT and IL-6-mediated Janus tyrosine Kinase (JAK)-STAT signaling pathway.⁴⁵ The clinical approval of tumor immunotherapies, particularly PD-1 blockade therapy, has garnered significant attention for treating solid tumors like CRC. TAMs significantly restrict the efficacy of anti-PD-1 therapy in CRC. Research indicates that inhibiting colony-stimulating factor 1 receptor (CSF1R) signaling reprograms M2 TAMs to an M1 phenotype. This repolarization promotes CD8⁺ T lymphocyte infiltration into tumors, ameliorates the immunosuppressive microenvironment, enhances the efficacy of PD-1 monoclonal antibody therapy, and prevents CRC recurrence by fostering long-term memory immunity.⁴⁶ Combination therapy with Foretinib and anti-PD-1 antibodies enhances T-cell infiltration and function, reduces TAMs, and inhibits their M2 polarization, thereby remodeling the TME to boost anti-CRC tumor immunity.⁴⁷ In macrophages, down-regulation of NF-κB activator 1 (Act1) activates STAT3, promoting colorectal adenoma-adenocarcinoma transformation through the CXCL9/10- C-X-C chemokine receptor type 3 (CXCR3) pathway in CRC cells and the PD-1/PD-L1 pathway in CD8⁺ T cells.⁴⁸ The STAT3 pathway is pivotal in CRC immunosuppression by regulating the recruitment of regulatory T cells (Treg) and M2-type TAMs. Combining STAT3 inhibitors with PD-1 antibody therapy disrupts the interaction between Treg and M2 TAMs, thereby enhancing anti-CRC tumor immunotherapy.⁴⁹ It follows that in the mid-term, research in the field of TAMs and CRC has focused chiefly on immunotherapeutic strategies for CRC and the mechanistic regulation of its immune microenvironment.

In the late phase (2019–2024), the research objectives and hot content are also the continuation and depth of the content of the mid-term, still focusing on immune checkpoint blockade and inhibitors, the specific mechanism of targeting TAMs to treat CRC and the therapeutic efficacy of combining related drugs, and at the same time, the study of the interactions with immune cells, such as CAFs, has been added. In addition, metabolism and CAFs become the most representative keywords in the later period. Metabolic reprogramming is an important hallmark of malignant tumors and a key mechanism for progression.⁵⁰ Tumor cells interact with multiple components of the TME by reprogramming metabolic pathways to meet the energy, biosynthesis, and redox requirements of tumor cells, mainly including glycolysis, amino acid metabolism, lipid metabolism, tricarboxylic acid cycle, and mitochondrial changes. Some papers have confirmed that metabolic interactions between TAMs and CRC cells can remodel the TME to promote CRC progression.⁵¹ For example, itaconic acid is a metabolite produced by pro-inflammatory isoforms of TAMs with pro-CRC effects.⁵² Ectopic expression of ABHD5, a lipolytic co-activator in CRC-associated TAMs, inhibits spermine production in macrophages dependent on spermidine synthase (SRM) by suppressing the reactive oxygen species-dependent expression of C/EBPɛ for CRC progression, confirming that the ABHD5/SRM/spermidine axis in TAMs may be a potential therapeutic target for CRC.⁵³ CAFs, the predominant stromal cells in the TME, are crucial core components similar to TAMs, exhibiting high heterogeneity and plasticity in both phenotype and function. CAFs facilitate tumor growth, angiogenesis, and ECM remodeling by secreting cytokines and interacting with stromal, tumor, and immune cells, including TAMs in other TMEs, as well as promote inflammation, suppress immune cell function, and modulate the tumor immune microenvironment, thereby advancing tumor development.^54,55 Research indicates that CAFs induce and mobilize M2 TAMs within the CRC tumor immune microenvironment, and both cell types collaboratively promote CRC progression.⁵⁶ Future papers on combined therapeutic strategies targeting these cells are crucial for advancing this field. Metabolic reprogramming and CAFs are key research areas in TAMs and CRC, with potential for further exploration of their mechanisms and targeted therapies.

At present, because the complex regulatory mechanism of TAMs in TME has not yet been fully clarified, a large number of related papers are still focusing on the mutual regulation between the mechanisms and remodeling of the oncogenic phenotypes of TAMs, and the development and translational application of clinical drugs targeting TAMs for the treatment of CRC are still in the initial exploration stage, which requires a longer road to go. At this stage, TAMs applied in the clinical treatment of CRC mostly play the role of predicting the progression or prognosis of CRC and assessing the clinical efficacy and treatment response. A clinical trial confirmed that primary rectal cancer expresses the CD163 phenotype, an M2 macrophage phenotype characterized by an association with early local recurrence, shortened survival time, and reduced apoptosis.⁵⁷ A single-arm, multicenter phase II clinical trial confirmed that the combination of Regorafenib and Avelumab mobilized anti-tumor immunity in some patients with microsatellite-stabilized CRC, whereas TAMs were significantly associated with poor progression-free survival and overall survival, and CD8⁺ T-cell infiltration was significantly associated with better outcomes.⁵⁸ Results from the TRIBE and FIRE3 trials confirmed that genetic variants regulating functions related to TAMs were significantly associated with clinical outcomes in patients with metastatic CRC receiving bevacizumab-containing chemotherapy.⁵⁹ CALGB/SWOG 80,405, a randomized Phase III clinical trial in patients with first-line metastatic CRC receiving chemotherapy with bevacizumab, cetuximab, or a combination of the two, demonstrated that increased M2-type macrophage scores and TGF-β signaling expression were associated with shorter overall survival.⁶⁰ Preoperative radiochemotherapy is essential to improve outcomes in patients with locally advanced rectal cancer, and a phase II ADORE study noted that preoperative radiochemotherapy activates the density of CD8⁺ T cells and dendritic cells in the tumor immune microenvironment to increase immunoreactivity, but at the same time can be immunosuppressive by polarizing TAMs from the M1 type to the M2 type and by decreasing the density of B cells.⁶¹ Thus, the TME in which TAMs are located is very complex, and the phenotypic remodeling of their anti-tumor and pro-tumor effects and their interactions with various immune cells are difficult to be precisely grasped, so it is difficult to fully elucidate their specific mechanism of action, and in the future, the application of cutting-edge technologies, such as single-cell transcriptomics and spatial proteomics, may play an important role in breaking through the field. At present, the role of targeted TAMs in CRC is still related to the prediction of CRC progression, prognosis and therapeutic efficacy, and it is necessary to continue to elucidate the complex mechanism of action in order to accurately regulate the TAMs, which will play a role in the research and development of drugs and the improvement of CRC clinical efficacy.

Due to the limitations of bibliometrics’ own research algorithms, emerging hotspots are less intense in their outbreaks, which can lead to many emerging fields and researchers’ contributions being neglected. Therefore, we try our best to mine the recent research hotspots from the analysis of keywords and try to show the latest research direction to the readers. In addition, self-citation bias may bias the results of the analysis. However, currently published bibliometric studies do not have a good solution to this problem, and we can only try to circumvent the bias caused by self-citation as much as possible. Regarding the issue of database restriction (WOSCC only), we used three bibliometrics-related software or toolkits to analyze the data, and the data exported by WOSCC is fully supported. However, the data exported by Scopus, PubMed, or Google Scholar have certain limitations for these tools and cannot support them simultaneously for in-depth analysis. As for the exclusion of non-English articles and books, this is because the high-quality results of TAMs and CRC research are mainly concentrated in English-language journals, and the number of non-English publications is so small that it is negligible. Moreover, the citation network of non-English literature is often confined to regional academic circles, and its citation indicators (e.g., H-index) are significantly different from the English literature system, and a mixed analysis may introduce bias.

Notably, each analysis software employed in this study has its strengths and limitations. CiteSpace 6.3 R1 is particularly effective in visualizing the clustering and temporal evolution of literature co-citations and keyword usage, making it useful for understanding intellectual structures and research frontiers. However, it is less suited for detailed analyses of collaborative networks. In contrast, VOSviewer 1.6.20 excels in mapping collaborative relationships among countries, institutions, authors, and journals through its intuitive visual network layouts, but offers limited timeline functionality. Bibliometrix, while not as strong in network visualization, provides flexible and comprehensive analysis features such as geographic distribution and authorship evaluation based on Lotka’s Law. By combining these tools, we aimed to leverage their respective advantages and mitigate individual limitations, allowing for a more comprehensive and multi-dimensional bibliometric analysis, particularly in the domains of co-authorship, co-occurrence, and co-citation.

In order to explore the evolutionary trajectory and investigative analysis in the fields related to TAMs and CRC, this paper adopts a more mature bibliometric method to visualize and preliminarily analyze the number of publications, authors, countries, institutions, journals, and references, and focuses on the keywords to analyze the research trend and future development direction. We believe that although the research on TAMs and CRC has made great progress, the specific mechanism of action is still unclear, and the clinical application at this stage is still in the aspects of diagnosis or prediction of efficacy and prognosis, and there is still a big gap from the strategy of precise targeting of TAMs for the treatment of CRC. Currently, the research on TAMs and CRC focuses on firstly clarifying the specific mechanism of action, integrating the most researched mechanisms such as NF-κB, endothelial growth factor, TGF-β, etc. with the research on TAMs and CRC, to form a complete chain of the mechanism of action or atlas, to find the key target or target, and to carry out drug research and development based on this. Secondly, as immune cells, TAMs should focus on their immunotherapeutic role in CRC, and PD-1/PD-L1 is the most widely studied immune checkpoint inhibitor, so future research can focus on exploring the mechanism of potentiation of TAMs in PD-1/PD-L1 immunotherapy for CRC. Thirdly, TAMs are located in the TME and interact with CD8⁺ T cells, CAFs, and other immune cells to play a role in the treatment of CRC. Exploration of the mechanism of interactions between immune cells from a holistic perspective is a new and critical direction for future research in this field. However, this paper also has certain limitations, which can be referred to and continuously improved in future research. First, in order to guarantee the caliber of the literature, although the literature information was retrieved from WOSCC, an authoritative database, it will lead to the omission of some literature information from other databases, which can not fully reflect the research trend in this field. Second, mistakes and omissions are inevitable, although duplicates or inaccuracies are corrected manually through double-proofreading. Third, bibliometrics’ own research algorithms have limitations, such as emerging hotspots that have just emerged and may be less intense outbreaks, which will lead to many emerging fields, and the contribution of the researcher is ignored. Fourth, with the use of different bibliometric software, there is information bias, and the results will have a certain degree of error and bias. Fifth, the lack of statistical validation of trends in postings over time could be a potential limitation.

Conclusion

In summary, this paper found that targeting TAMs for CRC has become an important area of oncology research and is undergoing rapid development by analyzing the number of publications, time, countries, institutions, authors, citations, and keywords of TAMs and CRC publications. The research themes in this field have transitioned from the initial phenotype and function of TAMs in CRC to the exploration of the key role targets or signaling pathways of TAMs, then to the later stage of combining with immunotherapy research such as PD-1 inhibitors, and then to the latest hotspot of research on the interactions with immune cells, such as CAFs, reflecting the trend and hotspot changes of the research in this field.

Future research should strengthen international cooperation on the basis of the previous research, focus on integrating and sorting out the current mechanisms and identifying key targets, and at the same time focus on the exploration of interactions with immunotherapy such as PD-1 and immune cells such as CAFs, to summarize and analyze the specific mechanism of action and putting it into clinical practice. Based on the current application of TAMs to predict the clinical efficacy and prognosis of CRC, we will truly develop therapeutic strategies and innovative drugs targeting TAMs to treat CRC, continuously improve the clinical efficacy of CRC and break through the bottleneck of the development of this field.

Biography

Zhongan Guan, Director of the Department of Anus and Intestines, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Famous Traditional Chinese Medicine Practitioner of Shandong Province, Renowned Expert, Professor, Chief Physician, M.D., PhD. He specializes in Chinese medicine, Chinese and Western medicine combined treatment of anal and intestinal diseases, especially in rectal tumors, constipation, ulcerative colitis and hemorrhoids, anal fistula, anal fissure and other unique insights.

Funding Statement

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Shandong Province Traditional Chinese Medicine Science and Technology Development Program Project [No. 2019-0070] and Qilu Chinese Medicine Advantageous Specialty Cluster Construction Project [No. YWC2022ZKJQ0003].

Disclosure statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Author contributions

YG: Investigation, Writing – original draft, Writing – review & editing; WY: Investigation, Writing – original draft, Writing – review & editing; JZ: Investigation, Writing – original draft, Writing – review & editing; ZW: Investigation, Writing – review & editing; ZG: Conceptualization, Methodology, Supervision, Writing – review & editing. All authors have read and approved the submitted version.

Data availability statement

In this paper, data sharing is not applicable as no new data were generated. The datasets utilized originated from publicly available resources: https://webofscience.clarivate.cn/wos/woscc/basic-search.

Statement

Our paper did not involve human participants, so ethical approval did not apply to our paper.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21645515.2025.2512656