Knowledge structure analysis and network visualization of tumor-associated macrophages in hepatocellular carcinoma research: A bibliometric mapping

Abstract

BACKGROUND

Tumor-associated macrophages (TAMs) have demonstrated significant potential as a research and treatment approach for hepatocellular carcinoma (HCC). Nevertheless, a comprehensive quantitative analysis of TAMs in HCC remained insufficient. Therefore, the objective of this study was to employ bibliometric methods to investigate the development trends and research frontiers pertaining to this field.

AIM

To determine the knowledge structure and current research hotspots by bibliometric analysis of scholarly papers pertaining to TAMs in HCC.

METHODS

The present study employed the Web of Science Core Collection to identify all papers related to TAMs in HCC research. Utilizing the Analysis Platform of Bibliometrics, CiteSpace 6.2.R4, and Vosviewer 1.6.19, the study conducted a comprehensive analysis encompassing multiple dimensions such as publication quantity, countries of origin, affiliated institutions, publishing journals, contributing authors, co-references, author keywords, and emerging frontiers within this research domain.

RESULTS

A thorough examination was undertaken on 818 papers within this particular field, published between January 1, 1985 to September 1, 2023, which has witnessed a substantial surge in scholarly contributions since 2012, with a notable outbreak in 2019. China was serving as the central hub in this field, with Fudan University leading in terms of publications and citations. Chinese scholars have taken the forefront in driving the research expansion within this field. Hepatology emerged as the most influential journal in this field. The study by Qian and Pollard in 2010 received the highest number of co-citations. It was observed that the citation bursts of references coincided with the outbreak of publications. Notably, “tumor microenvironment”, “immunotherapy”, “prognostic”, “inflammation”, and “polarization”, etc. emerged as frequently occurring keywords in this field. Of particular interest, “immune evasion”, “immune infiltration”, and “cancer genome atlas” were identified as emerging frontiers in recent research.

CONCLUSION

The field of TAMs in HCC exhibited considerable potential, as evidenced by the promising prospects of immunotherapeutic interventions targeting TAMs for the amelioration of HCC. The emerging frontiers in this field primarily revolved around modulating the immunosuppressive characteristics of TAMs within a liver-specific immune environment, with a focus on how to counter immune evasion and reduce immune infiltration.

Key Words: Tumor-associated macrophages; Hepatocellular carcinoma; Bibliometric analysis; Immune evasion; Immune infiltration

Core Tip: This is the first bibliometric study to investigate the publications on tumor-associated macrophages in hepatocellular carcinoma. The findings revealed knowledge mapping and identified research frontiers within this domain. The primary emphasis of the emerging frontier lay in the regulation of the immunosuppressive attributes exhibited by tumor-associated macrophages within the liver’s distinct immune milieu, with a specific focus on countering immune evasion and reducing immune infiltration.

INTRODUCTION

Liver cancer ranks as the second leading cause of cancer-related mortality worldwide, with hepatocellular carcinoma (HCC) being its predominant form[1]. While mortality rates for most cancers have decreased over the past four decades, HCC incidence and mortality have significantly increased[2], particularly in regions with a high prevalence of hepatitis B infections, such as China. Due to its insidious onset, HCC is often detected at an advanced stage, imposing a substantial health burden in China[3,4]. This trend underscores the critical need for improved therapeutic strategies. Current therapeutic strategies are limited, primarily comprising liver resection, transplantation, and targeted kinase inhibitors[5,6]. Research has shown that gene silencing or darapladib administration can reverse the immunosuppressive phenotype of tumor-associated macrophages (TAMs) in HCC, and enhance the efficacy of programmed cell death protein-1 inhibitors[7]. Although recent advances in immune checkpoint inhibitors (ICIs) combined with targeted therapies have demonstrated promising results in clinical trials, the overall survival rate for HCC patients remains suboptimal[8,9]. Furthermore, the intricate mechanisms underlying HCC immunotherapy, particularly the role of the tumor microenvironment (TME), are not fully understood, highlighting the necessity for further research[8,10,11].

TAMs, the representative of the liver immune cell population, assumes a central role in the initiation, progression, and metastasis of tumors. This revolutionary idea was substantiated by extensive research conducted over the past few decades[12,13]. TAMs were considered intricately associated with postoperative tumor progression and treatment outcomes[14-16]. For instance, preclinical targeting of TAMs via colony stimulating factor 1 receptor inhibition demonstrated dual benefits in tumor suppression and immunotherapy potentiation in HCC[17]. TAMs often exhibit a hybrid phenotype, displaying characteristics of both M1 and M2 types, and their functional states dynamically shift in response to the evolving TME. This plasticity is influenced by factors such as tumor type, stage, and the surrounding immune milieu[18,19]. Generally, TAMs exhibit characteristics akin to M2-type polarized macrophages which dampen immune responses[20]. However, TAMs demonstrate considerable dynamism and heterogeneity within the unique immune environment of hepatic tumors[21]. These functionalities encompass the regulation of signal transduction mechanisms, rapid response metabolic patterns, and cytokine secretion profiles[22]. Whether originating from the intrinsic response of TAMs, or intercellular communication between TAMs and cancer cells and the ensuing metabolic alterations, immunotherapeutic approaches targeting TAMs in HCC appear to hold substantial untapped potential and room for further investigation.

Bibliometrics, an emerging discipline within information science, employs quantitative and qualitative measures to investigate specific subject areas[23]. Its application in the medical field has become increasingly prevalent[24-26]. By utilizing visualizations of countries, institutions, journals, authors, common references, and co-occurring keywords, bibliometrics enables a comprehensive examination of knowledge structures and emerging trends within specific fields on a global scale. Despite the growing number of studies published in this domain, there remained a lack of comprehensive analysis of the current global research status in recent years. Consequently, this study aimed to employ bibliometric methods to elucidate the research knowledge structure and identify emerging hotspots of TAMs in HCC.

MATERIALS AND METHODS

Data source and searching strategy

The Web of Science Core Collection (WoSCC) was selected as the data source for retrieval due to its data integrity. The search strategy encompassed: TS = (“tumor-associated macrophages” OR “tumor-associated macrophage” OR “tumor associated macrophages” OR “tumor associated macrophage” OR “tumor-associated macrophages (tams)” OR “tumor-associated macrophage (tam)” OR “tumour-associated macrophage” OR “tumour-associated macrophage” OR “TAMs” OR “TAM”) AND TS = (“hepatocellular carcinoma” OR “HCC” OR “hepatocarcinoma” OR “hepatic cancer” OR “hepatic carcinoma” OR “hepatoma” OR “liver cancer” OR “liver carcinoma” OR “liver cell carcinoma”). The search was further refined to include only publications categorized as “article” or “review”, in English, and published between January 1, 1985 and September 1, 2023. In order to mitigate potential bias resulting from regular database updates, the retrieval was completed in a single day. The selection of this timeframe was based on three considerations: (1) Capturing foundational studies from the earliest available WoSCC record (January 1, 1985); (2) Tracing changes in research hotspots through longitudinal analysis; and (3) Identifying emerging trends over 38 years of scholarly discourse. A total of 818 records were obtained in the “full record and cited reference” format. To ensure precision in the bibliometric analysis, two authors conducted data extraction using the aforementioned search strategy. Prior to further bibliometric analysis, the thesaurus data were consolidated. Any conflicting perspectives were resolved through team discussion.

Bibliometrics and visualization analysis

The information pertaining to publication quantity, countries of origin, affiliated institutions, publishing journals, contributing authors, co-references, and author keywords was extracted from the original dataset. The Analysis Platform of Bibliometrics package[27] was utilized for conducting descriptive analysis on publications, citations, and H-index. Data processing was performed with Microsoft Office Excel 2019, and a polynomial regression model was developed to predict the number of papers in 2023. Scholarly impact was assessed through various indicators, including outputs, citations, and H-index, etc. In order to conduct a comprehensive analysis of the structural composition of co-research networks, including clusters, inter-cluster connections, and pathways, as well as to assess the impact and importance of references and author keywords, the software tools VOSviewer 1.6.19[28] and CiteSpace 6.2.R4[29] were employed. The detection feature in CiteSpace 6.2.R4 was utilized to identify keywords and references that exhibited significant citation bursts. The literature screening and data analysis process is illustrated in the flow chart depicted in Figure 1.

Figure 1 Flowchart depicting the search process employed. WoSCC: Web of Science Core Collection.

RESULTS

Analysis of annual paper outputs

A comprehensive analysis of the WoSCC, based on the specified search parameters, identified 818 papers. As depicted in Figure 2A, the initial publication in this field emerged in 1994, with a consistent increase in the number of papers observed since 2012, culminating in a significant surge in 2019 (average growth rate of 14.63%). The period between 2012 and 2023 accounted for 91.9% of the total publications, with 752 papers produced during this time. The peak annual publication count was recorded in 2022 (n = 137, 16.7%). To illustrate this trend, a growth model was developed based on historical data (y = 2.18 × 10^-165 × e^0.1899x, R² = 0.9844, where y represents the annual paper count and x denotes the year). Projections based on this model suggest that 151 papers will be published cumulatively in 2023, with 105 papers already released.

Figure 2 Bibliometric analysis conducted on publications. A: Annual outputs of publications and growth forecast; B: Annual outputs of publications of the top 10 countries.

Analysis of distribution of countries/institutions

A total of 818 papers were produced from 50 different countries. The top ten countries that made contributions in this field are presented in Figure 2B. In terms of paper outputs (Table 1), China emerged as the frontrunner with 513 papers, followed by the United States with 118 papers. Additionally, China received the highest citations with 20006, followed by the United States with 9336 citations, maintaining consistency between publications and citations. The global distribution of research on TAMs in HCC is visually represented in Figure 3A. Furthermore, China ranked first in both single-country papers and multiple-country papers, as depicted in Figure 3B. The manifestation of cooperative relationships among countries is depicted in Figure 3C, while Figure 3D illustrates the co-authorship network among countries. These findings unveiled China’s pivotal role as the central hub within this domain, as well as its robust collaborations with the United States.

Figure 3 Bibliometric analysis conducted on countries/institutions. A: Map of collaboration countries; B: Top ten countries with the highest number of corresponding authors; C: Co-authorship visualization among countries. Circles’ size and color represent outputs and the average year of publication, respectively; D: Co-authorship visualization among institutions. Circles’ size and color represent outputs and the average year of publication, respectively.

Table 1 Top 10 countries/institutions related to tumor-associated macrophages in hepatocellular carcinoma research.

Country	Output	Citations	Organization	Location	Output	Citations
China	513	20006	Fudan University	China	67	3667
United States	118	9336	Sun Yat Sen University	China	35	1158
Japan	54	2992	Zhejiang University	China	31	983
Italy	42	2861	Shanghai Jiao Tong University	China	27	2210
Germany	37	2298	Nanjing Medical University	China	24	905
United Kingdom	22	717	Shandong University	China	23	1064
Korea	19	473	Central South University	China	23	473
France	15	848	Huazhong University of Science and Technology	China	21	810
Spain	14	878	Chinese Academy of Sciences	China	20	1421
Singapore	14	846	Peking Central South University	China	16	846

A total of 1071 institutions contributed to the production of these papers. The top 10 institutions of publication outputs all were affiliated with China, with a minimum of 16 papers produced (Table 1). Fudan University emerged as the leading institution in terms of publication outputs, with a count of 67. Meanwhile, Fudan University also gained the highest citations, amounting to 3667, followed by Shanghai Jiao Tong University with 2210 citations. The co-authorship network among institutions is depicted in Figure 3D, revealing a strong cooperative relationship between different establishments, such as Nanjing Medical University and Nanjing University. Notably, Central South University stood out as a representative institution with a notable concentration of publication outputs in recent years. The size and color intensity of the circles in the figure denote the annual volume of papers and publication time.

Analysis of journals and co-cited journals

These papers were sourced from a total of 323 journals. Using Bradford’s law (Figure 4A), a total of 20 journals were identified as core journals. Among these core journals, Frontiers in Immunology ranked first with the highest number of published papers (n = 37), indicating its significant influence in the field. On the other hand, Cancer Research was the most frequently cited journal (n = 2285). Additionally, Hepatology demonstrated a notable impact with an H-index of 16, followed closely by Frontiers in Immunology with an H-index of 15 (Table 2). The co-citation analysis of journals is visually presented in Figure 4B, wherein four distinct clusters were observed. The interconnectedness of cited journals within the network illustrates the relationships between two journals. The magnitude of nodes reflects the frequency of co-citations. Notably, journals within the same color-coded cluster exhibits a notable thematic similarity, such as cluster yellow, which represents professional journals on liver diseases. A dual-map overlay was employed, wherein the colored path symbolizes the cited relationship between citing and cited journals. The size of the circles within the overlay corresponds to the number of papers and authors within a particular field. The greater the number of authors, the longer the horizontal axis of the circle. It is worth noting that studies originating from journals focused on molecular biology and immunology were frequently cited by studies from molecular biology and genetics journals, as indicated by the orange citation paths. Likewise, the green paths demonstrates that studies from molecular biology and genetics journals were commonly cited by studies from medicine, medical, and clinical journals (Figure 4C).

Figure 4 Bibliometric analysis conducted on journals. A: Twenty core journals identified using Bradford’s law; B: Co-citation visualization among journals. Circles’ size and color correspond to citations and clusters, respectively; C: Dual-map overlay visualization of journals. Colored path indicates the cited relationship.

Table 2 Top 10 journals of impact related to tumor-associated macrophages in hepatocellular carcinoma research.

Journal	H-index	Output	Citations	IF (2022)	JCR quartile
Hepatology	16	20	1754	13.5	Q1
Frontiers in Immunology	15	37	730	7.3	Q1
Cancer Letters	11	17	688	9.7	Q1
International Journal of Molecular Sciences	11	22	412	5.6	Q1
Journal of Hepatology	11	13	1043	25.7	Q1
Oncology Letters	10	14	166	2.9	Q3
Cancer Immunology Immunotherapy	9	10	338	5.8	Q1
Cancer Research	9	10	2285	11.2	Q1
Cancers	9	17	367	5.2	Q2
Frontiers in Oncology	8	13	316	4.7	Q2

IF: Impact factor; JCR: Journal Citation Reports.

Analysis of authors and co-cited authors

A comprehensive analysis of records revealed that 5611 authors published relevant papers in this field. The application of Lotka’s law, a measure of scientific productivity, demonstrated that 81.4% of authors contributed only one paper (Figure 5A). Notably, Chinese scholars have taken the forefront in driving the research expansion within this field. Dr. Fan Jia from Fudan University participated in the highest outputs of relevant papers, totaling 16. On the other hand, Dr. Hui-Chuan Sun from Fudan University garnered the highest citation count, with a total of 1178 citations (Table 3). The analysis of the co-authorship network among institutions indicated that collaborative relationships were primarily concentrated within individual research teams (Figure 5B). Furthermore, the co-citation analysis highlighted that Alberto Mantovani from Humanitas University had the highest count of co-citations (n = 429, Figure 5C).

Figure 5 Bibliometric analysis conducted on authors. A: Scientific productivity of authors based on Lotka’s law; B: Co-authorship visualization among authors. Circles’ size and color represent outputs and clusters, respectively; C: Co-citation visualization among authors. Circles’ size and color represent citations and clusters, respectively.

Table 3 Top 10 authors with highest outputs, citations, and co-citations related to tumor-associated macrophages in hepatocellular carcinoma research.

Author	Output	Author	Citations	Co-author	Co-citations
Fan Jia	16	Sun Hui-Chuan	1178	Alberto Mantovani	429
Zhou Jian	15	Zhu Xiao-Dong	1160	Josep M Llovet	232
Zhang Jian	12	Zhang Wei	987	Antonio Sica	179
Sun Hui-Chuan	9	Tang Zhao-You	984	Qian Bin-Zhi	143
Zheng Li-Min	9	Fan Jia	949	Kuang Dong-Ming	132
Zhu Xiao-Dong	8	Wang Lu	874	Subhra K Biswas	111
Gao Qiang	7	Wu Wei-Zhong	874	Wan Shanshan	111
Wang Xue-Hao	7	Shirabe Ken	813	Richard S Finn	107
Yang Yang	7	Zhuang Peng-Yuan	800	Zhou Shao-Lai	105
Li Yan	6	Maehara Yoshihiko	783	Roy Noy	99

Analysis of co-cited references

A total of 43187 co-cited references were analyzed, with 119 of them being co-cited at least 20 times and visually represented in Figure 6A to depict their mutual cited relationships. Table 4 presents the top 10 co-cited references, with the highest number of citations attributed to Qian and Pollard[30] (n = 630). They comprehensively elucidated the mechanisms by which macrophages contribute to the initiation and progression of tumors, while also suggesting that specific subpopulations of macrophages hold promise as novel therapeutic targets[30]. Figure 6B displays the top 25 references exhibiting the strongest citation bursts, which served as indicators of the knowledge structure pertaining to the research focus within the field. The onset of citation bursts could be traced back to 2012, with a notable surge in references of citation bursts between 2019 and 2023, indicating that a research boom began during this period. This observation aligned with the analysis of annual publication outputs, wherein seven references were still in the burst. Among these references, the paper by Noy and Pollard[13] demonstrated the most substantial burst with a strength value of 10.81. This paper elaborated on TAMs from mechanism to therapy, and extensively discussed the role of macrophages in tumor treatment and proposed their potential as an attractive target in combination therapies[13]. Additionally, this reference garnered the second highest citations in co-cited reference analysis (n = 493).

Figure 6 Bibliometric analysis on co-cited references. A: Co-citation visualization among references. Circles’ size and color represent citations and clusters, respectively; B: Top 25 co-cited references with the strongest citation bursts.

Table 4 Top 10 most co-cited references related to tumor-associated macrophages in hepatocellular carcinoma research.

Ref.	Type	Citations	IF (2022)
Qian and Pollard[30], 2010	Review	630	64.5
NOY and Pollard[13], 2014	Review	493	32.4
Mantovani et al[34], 2002	Review	348	168.9
Wan et al[56], 2014	Basic research	347	29.4
Mantovani et al[20], 2017	Review	335	78.8
Llovet et al[57], 2008	Clinical research	311	158.5
Pollard[58], 2004	Review	309	78.5
El-khoueiry et al[35], 2017	Clinical research	301	168.9
Kuang et al[59], 2009	Basic research	294	15.3
Zhu et al[60], 2008	Clinical research	292	45.4

IF: Impact factor.

Analysis of author keywords and hotspots

A cumulative sum of 1559 author keywords were identified in this research field. After merging the thesaurus, certain terminologies such as “tumor-associated macrophages”, “hepatocellular carcinoma”, and “tumor microenvironment” were retained, while insignificant keywords like “cancer”, “tumor”, and “liver” were eliminated. These keywords serve as indicators of the subject matter and research content of the papers. By examining the occurrence of author keywords, the focal points and prevailing trends could be efficiently grasped in a specific field of study. In Figure 7A, author keywords were categorized into two distinct clusters. The highest occurrences included “tumor microenvironment” (n = 152), “immunotherapy” (n = 89), “prognostic” (n = 55), “inflammation” (n = 33), and “polarization” (n = 33), among others (Table 5). These keywords primarily centered around the biology and function of TAMs in HCC. The utilization of the keyword timeline viewer facilitated the examination of the progression of these keywords across various clusters. Figure 7B depicts the temporal extent and dispersion of keywords within this domain, thereby unveiling temporal patterns and interconnections. Nodes of different hues positioned on the same line correspond to distinct years, with the red nodes denoting keywords exhibiting the most pronounced citation bursts. Moreover, Figure 7C illustrates the top 25 author keywords that demonstrated the strongest citation bursts, serving as crucial indicators for identifying research hotspots and emerging frontiers. Notably, bursts keywords such as “immune evasion” (n = 5.09), “immune infiltration” (n = 4.78), and “cancer genome atlas” (n = 4.7) were prominently emphasized and considered the current research hotspots.

Figure 7 Bibliometric analysis on author keywords. A: Co-occurrence visualization among author keywords. Circles’ size and color represent the frequency of occurrences and clusters, respectively; B: Timeline scope of co-citation analysis of author keywords. Nodes on the same timeline represent years; C: Top 25 author keywords with the strongest citation bursts. HCC: Hepatocellular carcinoma; TAMs: Tumor-associated macrophages; TME: Tumor microenvironment.

Table 5 Top 20 author keywords related to tumor-associated macrophages in hepatocellular carcinoma research.

Rank	Keyword	Occurrences	Total link strength	Rank	Keyword	Occurrences	Total link strength
1	HCC	338	1210	11	NF-kappa B	20	76
2	TAMs	223	855	12	Tamoxifen	19	51
3	TME	152	624	13	Angiogenesis	18	106
4	Immunotherapy	89	379	14	M2 macrophages	18	60
5	Prognostic	55	194	15	Biomarkers	17	75
6	Inflammation	33	124	16	PD-L1	17	78
7	Polarization	33	115	17	Immune infiltration	16	54
8	EMT	30	118	18	Immunosuppression	15	76
9	CSCs	26	107	19	MicroRNA	14	67
10	Metastasis	21	102	20	Exosomes	14	59

HCC: Hepatocellular carcinoma; TAMs: Tumor-associated macrophages; TME: Tumor microenvironment; EMT: Epithelial-mesenchymal transition; CSCs: Cancer stem cells; NF: Nuclear factor; PD-L1: Programmed death ligand 1.

DISCUSSION

General information

The literature pertaining to TAMs in HCC was comprehensively examined using the WoSCC database, encompassing the period from January 1, 1985 to September 1, 2023. This bibliometric study included 818 publications authored by 5611 scholars affiliated with 1071 institutions from 50 different countries. These publications were distributed across 323 journals and covered a range of 1559 keywords and 43187 co-cited references. Significantly, the examination and analysis of HCC through the lens of TAMs had not garnered substantial scholarly attention prior to 2012. However, following a period of consistent growth between 2012 and 2018, the outputs of publications in this field had experienced a rapid expansion since 2019. This trend underscored the emergence of studying HCC from the perspective of TAMs as a distinct and burgeoning research field.

The field of international cooperation in this domain showed a high level of collaboration. The examination of studies revealed that China was the central hub of this field, which may be closely related to the actual situation. Epidemiological data from 2020 underscored that liver cancer remained the second leading cause of mortality in China. Scholars are presently directing their attention towards the regulation of TAMs with the aim of attaining a comprehensive understanding of HCC, making it a dynamic and rapidly developing research field. This assertion was further substantiated by an analysis of institutional contributions, wherein the top 10 institutions with the greatest publication output all emanated from China. A strong collaborative network was observed among research institutions, with Fudan University emerging as a prominent leader in terms of publications and citations. The number of publications and citations of the core institutions in this field were generally consistent, except for Central South University. However, given the institution’s high output in recent years, it was anticipated that its citations may improve over time. Notably, the majority of institutions with research foundations in this field are located in the Yangtze River delta region, such as Fudan University, Zhejiang University, Shanghai Jiao Tong University, and Nanjing University. Moreover, this region is recognized as one of the most prosperous economic zones in China.

The Bradford’s law and H-index were utilized as standard approaches to evaluate core journals. The findings indicated a general alignment, as represented of the core journals Hepatology, Frontiers in Immunology, and Cancer Research. In particular, Frontiers in Immunology held a prominent position as a burgeoning representative journal within the domain of immunology, boasting the highest publication outputs and the second highest H-index in this field. It is plausible to anticipate that the journal’s influence will further escalate as citations steadily augment in the forthcoming years. Furthermore, core journals exhibited substantial influence, with a significant proportion falling within first quartile of the Journal Citation Reports. This observation suggested that research in this field held considerable significance within the global academic community. But it was evident that research papers in this field published in prestigious journals like Cell (with 2 publications and 1231 citations) tended to garner more attention from scholars and receive a higher number of citations. Additionally, co-journals could be classified according to various categories, including liver diseases, immunology, oncology, etc., which primarily encompassed disciplines such as medicine, molecular biology, and immunology. Regarding scholarly outputs and citations, the majority among the top ten authors were from China. However, the situation was reversed when considering co-citations analysis. This observation suggested that the pioneering scholarly contribution in this field did not originate from Chinese scholars, but rather Chinese scholars led the research boom. Among them, Dr. Fan Jia, a distinguished scholar, has emerged as a prominent leader in liver cancer research within China due to his prolific and impact publication record. His notable contributions encompassed substantial advancements in elucidating the molecular mechanisms that govern the regulation of the HCC microenvironment[31,32]. Moreover, his research team extensively investigated the intricate molecular mechanisms underlying the immunosuppressive effects exerted by TAMs in HCC[33].

In term of references analysis, it becomes apparent that a considerable proportion of co-citation references were authored by highly cited scholars. For instance, Dr. Alberto Mantovani, as the first author, had contributed two papers that ranked among the top 10 co-citation references. Mantovani et al[34], ranking second with a total of 348 co-citations, explored the concept that TAMs are a paradigm for polarized M2 macrophages. By manifesting the characteristic features of polarized M2 cells, TAMs assumed a pivotal role in inflammatory circuits that facilitated tumor progression and metastasis[34]. Mantovani et al[20], which ranked fifth with a total of 335 co-citations, explored the potential of TAMs as a viable target for tumor treatment and offered therapeutic strategies. They considered that TAMs could be utilized as a means to customize the application of cell reduction therapies and immunotherapies, aligning with the principles of personalized medicine. Moreover, treatment strategies centered around TAMs possessed the capacity to complement and synergize with existing chemotherapy and immunotherapy approaches[20]. Significantly, the majority of the top 10 high-citation references predominantly consisted of reviews, with a predominant focus on providing comprehensive summaries of the biological functionalities exhibited by TAMs. These findings can serve as a fundamental framework and guiding principle for further investigations in the field of HCC. Overall, the examination of outputs, countries, institutions, journals, authors, and co-references, contributed to the establishment of a comprehensive knowledge mapping pertaining to this field. By understanding the complex interconnections of knowledge structure, researchers can develop a more profound comprehension of the dynamic field of TAMs in HCC research.

Research frontiers and trends

Bibliometric analysis has proven to be a valuable tool for evaluating research trends and emerging research areas. It aids in identifying references and keywords for the strongest bursts that experience a timeline, thereby indicating the current focal points within the field. The majority of the references in bursts belonged to original research, particularly emphasizing the research and treatment applications for HCC, as compared to the top 10 highest-citation references. It is worth noting that two of these were clinical studies. Of particular importance was the paper by El-khoueiry et al[35] (strength = 7.09), which emerged as the most influential burst reference, indicating therapeutic potential of nivolumab, a programmed cell death protein-1 ICI, in the treatment of advanced HCC. This was also among the top ten co-references. Another was published by Bruix et al[36] (strength = 3.59), and it demonstrated that regorafenib exhibited a significant survival advantage in patients with HCC who had previously received sorafenib treatment. This finding signified the notable progress made in the field of systemic treatment research for HCC in recent years, as evidenced by numerous successful clinical trials and the approval of several drugs for clinical application. Furthermore, in May 2020, the United States granted approval for the utilization of Atezolizumab plus Bevacizumab therapy as the primary treatment for unresectable HCC, signifying the commencement of a new era in combined immune-targeted therapy[37]. Similarly, a dual regimen involving the combination of Sintilimab and a bevacizumab analog has been developed[38]. Concurrently, numerous ongoing clinical trials are also contributing to the expansion of potential therapeutic agents and the exploration of multi-modal approaches for the diagnosis and treatment of HCC.

However, a subset of HCC patients exhibit resistance to immunotherapy, and the underlying mechanism remains elusive[8,39,40]. Notably, within the burst references, two seminal basic studies were noteworthy. Wu et al[41] (strength = 4.74) elucidated the reversal of cancer immunosuppression and anti-programmed cell death ligand 1 resistance through the blockade of triggering receptor expression on myeloid cell-1 in hypoxia-induced TAMs. This study provided partial insights into the resistance mechanism to immunotherapy from the perspective of TAMs. Additionally, Ma et al[42] (strength = 3.72) showed that tumor cell biodiversity drove cancer microenvironment reprogramming. Furthermore, two reviews also featured comprehensive evaluations of the current research landscape pertaining to the immunosuppressive TME and TAMs in HCC. Specifically, Tian et al[21] delved into an in-depth analysis of the involvement of macrophages in the initiation and progression of HCC, alongside summarizing potential immunotherapeutic approaches targeting these macrophages. Lu et al[43] provided a thorough analysis of immunosuppressive cells, namely, TAMs, myeloid-derived suppressor cells, tumor-associated neutrophils, and cancer-associated fibroblasts, and their interactions with regulatory T cells, which played an active role in promoting tumorigenesis. Additionally, this review delves into the current treatment approaches and highlights potential avenues of HCC for future research.

The most frequently occurrence keywords in this field were TME, immunotherapy, prognostic, inflammation, polarization, etc. The top 25 keywords were closely associated with the biological function and corresponding treatment strategies of TAMs. The monocyte-macrophage lineage is integral to the maintenance of liver homeostasis and the facilitation of rapid responses to hepatic injury[44]. Additionally, HCC has been recognized as an inflammation-associated cancer[1]. Recruited macrophages and tissue-resident macrophages (Kupffer cells) play a significant role in linking inflammation and HCC[45]. Macrophages that infiltrate the tumor tissue undergo a transformation into TAMs, playing a pivotal role as a crucial constituent of the TME[46]. Upon acquiring immunosuppressive and tumor-promoting phenotypes, TAMs collaborate with non-malignant cells to facilitate tumor cell proliferation, invasion, and metastasis. This intricate interplay extends to TAMs’s interaction with liver cancer cells, as well as their communication with other immune cells through direct cell-to-cell contact or the secretion of various effector molecules[47-49]. Furthermore, the interaction between tumor cells and other immune cells can induce the recruitment and polarization of TAMs[50]. In conclusion, TAMs have a surprising impact on the onset and progression of HCC, with their biological functions encompassing immunosuppression, promotion of tumor invasion and metastasis, angiogenesis, induction of epithelial-mesenchymal transition, and maintenance of stem cells.

Given the inherent heterogeneity of TAMs in HCC and their intricate communication with cells within the TME in the liver, the current research frontiers lie in devising strategies to counteract TAMs-induced immune evasion and effectively manage the significant immune infiltration in liver cancer tissues. Moreover, the emergence of bioinformatics, particularly The Cancer Genome Atlas database, has positioned itself as an indispensable scientific research tool in recent years[51]. The immunosuppressive characteristics exhibited by tumor lesions not only serve as significant contributors to tumor advancement but also pose a substantial obstacle to successful immunotherapy[13]. Consequently, potential therapeutic strategies aimed at targeting TAMs encompass inhibiting the recruitment and survival of macrophages within tumors, re-educating TAMs to adopt an anti-tumor “M1-like” phenotype, manipulating TAMs to express checkpoint proteins that regulate T cell activation and serve as targets for checkpoint blocking immunotherapies, and employing tumor-targeting monoclonal antibodies that induce macrophage-mediated extracellular killing or phagocytosis, leading to intracellular destruction of cancer cells[12,21,52].

Hence, a comprehensive understanding of the involvement of TAMs in HCC is imperative for the advancement of efficacious therapeutic approaches. Initial findings from pharmacological interventions targeting TAMs indicated the potential for successful translation into novel treatment regimens for HCC patients[16,53,54]. In the near future, the targeting of TAMs holds promise for introducing innovative concepts in adjuvant immunotherapy for individuals with HCC. Despite the promising findings from existing research on TAMs, the utilization of TAMs as a specific therapy for HCC still faces certain challenges[12,55]. Further investigation into TAMs in the context of HCC is warranted, particularly regarding their intercellular communication with cancer cells, metabolic alterations, and inherent biological stress. In the future, the advancement of liver-specific immune environment-targeting drugs for TAMs and the development of more reliable, secure, and effective immune-combination therapies will facilitate the progress of immunotherapy for HCC.

Strengths and limitations

This study represented the inaugural bibliometric analysis conducted on the field of TAMs in HCC, offering an impartial and comprehensive examination while identifying the knowledge mapping and research frontiers within this domain. Consequently, it possessed the capacity to function as a noteworthy asset for scholars involved in this particular field. Nevertheless, our examination solely focused on scholarly outputs obtained from the WoSCC and limited to English-language publications. This approach may have excluded relevant studies published in other languages or indexed in alternative databases such as PubMed, Scopus, and Embase, potentially introducing a language and database bias. Also, the selection of keywords, while carefully considered, might not have captured all relevant studies due to variations in terminology or indexing practices. Furthermore, considering the nascent state of this discipline, it is important to acknowledge that the current scarcity of citations might inadvertently exclude potentially valuable published papers. Despite these limitations, our study provides a foundational overview of the current research landscape. We aim to address these constraints in future research to ensure a more comprehensive analysis.

CONCLUSION

From 1985 to 2023, there has been a persistent upward trend in the quantity of papers focused on TAMs in HCC. This trend suggested that research in this area is currently undergoing a dynamic and rapidly progressing phase. Scholarly efforts in recent years have made substantial contributions to the advancement of this field. The present study offered the inaugural bibliometric analysis of scholarly papers pertaining to TAMs in HCC, thereby revealing prevalent research networks, developmental patterns, and current research hotspots. Immunotherapeutic interventions aimed at targeting TAMs for the purpose of improving HCC showed promise, thus presenting a significant research potential. The emerging frontiers in this field primarily centered on manipulating the immunosuppressive properties of TAMs within the liver-specific immune milieu, with an emphasis on overcoming immune evasion and decreasing immune infiltration. The results of this study provide valuable insights for scholars to pursue additional research in this area.