We used the Web of Science database to search for relevant literature. To avoid bias caused by database updates, all of the literature and related data were downloaded manually on September 1, 2023. The search conditions were as follows. The publication date ranged from September 1, 2003 to September 1, 2023. We limited the search type to Article and the language to English. TS=(“liver neoplasm *” OR “hepatic cancer” OR “liver cancer” OR “hepatic cancer *” OR “hepatic cancer *” OR “hepatic cancer *” OR “hepatic cell cancer *”) AND TS=(“Tumor Microenvironment *” OR “Cancer Microenvironment *” OR “Cellular Microenvironments” OR “Cell Microenvironment *”). The retrieval process is shown in Figure 1 .

VOSviewer and CiteSpace are classic bibliometric analysis software. Unlike other visual mapping programs, VOSviewer pays special attention to the graphical representation of bibliometric maps, and is suitable for displaying large bibliometric maps in an easy to interpret manner (10). However, the purpose of Citespace is to assist clinical researchers in generating domain-specific datasets, aiming to facilitate the analysis of emerging trends in selected fields (11). They can support various types of bibliometric research, including co-citation analysis, co-occurrence analysis, and burst analysis. In this study, we first completed the co-authorship analysis and co-occurrence analysis by using VOSviewer1.6.18, and established a visual map. In addition, we also completed a descriptive analysis of publication year, countries, institutions, journals, authors, and references. Finally, we used CiteSpace 6.2.R6 to perform the timezone map analysis and burst analysis on keywords.

We retrieved a total of 2,157 articles related to the TME of HCC and included them in the final study analysis. The trend of publications from 2003 to 2022 is shown in Figure 2 , thus demonstrating an overall upwards trend. Via linear regression analysis, we predict that the total number of publications in 2023 will reach approximately 544. According to this prediction, the total number of publications from 2021 to 2023 will be approximately 1,394, which accounts for 64.63%. This indicates that research related to the TME of HCC has received increasing amounts of attention.

Between 2003 and 2023, a total of 580 academic journals with published articles related to the TME of HCC were identified. We list the top 10 journals with the most published articles and related impact indicators in Table 1 . The most publications originated from Frontiers in Immunology (n=75). Hepatology is the journal with the highest total number of citations (n=4,104), and its impact factor (IF=13.5) is also the highest, thus indicating that the quality of the articles in this journal is relatively high and that it is authoritative in the research field. The journals in the Frontiers series had the highest average publication year, thus indicating that this series of journals has shown great interest in the field and that the number of related articles has shown rapid growth in recent years.

Fifty-four countries throughout the world have participated in research related to the TME of HCC, and we list the top 10 countries with the greatest number of publications in Table 2 . China is the most productive country (n=1,525, 70.7%). Moreover, China is also the country with the highest total number of citations (n=32,253, 61.7%). The number of publications and the total number of citations from China both accounted for more than 60%, which indicated that Chinese scholars have made significant contributions to research in this field.

In addition, we conducted a co-authorship analysis of 54 countries and regions by using VOSviewer. As shown in Figure 3 , both China and the United States cooperate with 34 countries and regions, followed by Italy with 23. China and the United States have a significant influence on international cooperation.

According to our data analysis of the collected literature, a total of 2,081 institutions participated in the publication of papers related to the TME of HCC, and the top 10 institutions in terms of publication volume are shown in Table 3 . These 10 institutions originated from China, with Fudan University having the highest number of publications (n=135). Fudan University also has the highest total number of citations (n=4,541), thus demonstrating its authority and outstanding contribution in this research field. In addition, Zhengzhou University has the highest average publication year and has good research potential in this field.

We set the minimum number of publications to 10, identified 92 high-yield institutions from 2,081 institutions, and conducted a co-authorship analysis on these 92 high-yield institutions by using VOSviewer. As shown in Figure 4 , Shanghai Jiao Tong University may be the most influential institution in terms of collaboration, wherein it collaborated with 40 high-yield institutions.

Table 4 shows the top 10 authors in terms of publication volume in research related to the TME of HCC. Fan Jia and Zhou Jian are the authors with the greatest number of publications, each with 36 articles. These two scholars also have the most total citations (Fan Jia [n=2,127] and Zhou Jian [n=1,886]), thus indicating that their research results are widely recognized and may be authoritative representatives in the field.

We set the minimum number of publications to 5, identified 219 high-yield authors from 10,641 authors, and conducted a co-authorship analysis on these 219 high-yield authors by using VOSviewer. Fan Jia and Zhou Jian collaborated with 35 high-yield authors, wherein they ranked first ( Figure 5 ).

We list the top 10 articles with the greatest number of citations in Table 5 , of which 5 are from China, 3 are from the United States, and the remaining 2 are from Japan and Italy. Chinese scholars have made outstanding contributions to and influence on the field of the TME in HCC.

It is worth mentioning that the article “Phase Ib Study of Lenvatinib Plus Pembrolizumab In Patients With Unresectable Hepatocellular Carcinoma”, which ranked first in citation count, was published in July 2020 and increased to the top spot in just three years. These results are highly significant, and the attention and expectations of global researchers are gradually shifting towards combination therapy.

We extracted a total of 6,846 keywords from these 2,157 articles. To more intuitively and quickly obtain the frontiers and hotspots of research related to the TME of HCC, We set the minimum number of keyword occurrences to 20, conducted co-occurrence analysis on 151 high-frequency keywords that met the conditions, and constructed a co-occurrence network diagram of high-frequency keywords. As shown in Figure 6 , these high-frequency keywords are mainly divided into four clusters, as represented by different colours. By integrating the keyword frequency within each cluster and the average co-occurrence year, we determined the research focus for each cluster. The red clusters represent the main components and roles in the TME of HCC, such as “extracellular matrix”, “cancer-associated fibroblasts” and “hepatic stellate cells”; the green clusters represent immunotherapy for HCC, such as “immunotherapy”, “PD-1” and “immune cells”; the yellow clusters represent combination therapy for HCC, such as “combination therapy”, “targeted therapy” and “resistance”; and the blue clusters represent the microenvironmental landscape of HCC, such as “landscape”, “immune infiltration” and “heterogeneity”.

In addition, we also found that the keyword “cell death” has seen a spike in citations over the last three years ( Figure 7A ). Related keywords such as “ferroptosis”, “biomarker” and “diagnostic signature” appeared around 2022 ( Figures 7B, C ). It shows that these research directions have received increasing attention in recent years and may become the research hotspots in the future.

In this study, we identified literature studies on the TME of HCC over the past 20 years in the Web of Science database (2003-2023). After excluding studies that did not meet the screening criteria, a total of 2,157 English studies published in 580 academic journals and from 2,081 institutions in 54 countries were included.

The number of publications related to the TME of HCC has been increasing annually, especially in the past three years, when the number of publications exceeded 300. According to linear regression analysis, the total number of publications from 2021 to 2023 will reach approximately 1,394, accounting for 64.63%. We believe that the main reason for this explosive growth involves the breakthrough of immunotherapy in HCC. In addition, it is worth noting that among the top ten cited articles, “Phase Ib Study of Lenvatinib Plus Pembrolizumab In Patients With Unresectable Hepatocellular Carcinoma” is the only clinical trial study, and this article risen to the top of the list in just three years since its publication. The focus and expectations of global researchers are gradually shifting towards combination therapy, especially the combination of ICIs and other drugs.

Based on the general information distribution of the collected literature, China ranks first in the world, whereas the United States and Japan rank second and third respectively. The point worth emphasizing is that the number of publications and the total number of citations from China exceed those from other countries combined ( Table 2 ), and the top 10 research institutions and scholars in terms of publications are all from China ( Tables 3 and 4 ). China has invested a lot in research in this field. We believe that the potential reason is that the five-year survival rate of Chinese patients with liver cancer is low, less than 15% (12), and new cases account for approximately half of the global total (13). In an effort to enhance survival rates and improve prognoses, Chinese institutions and scholars are dedicated to research in this field. Among them, Fudan University’s contribution is particularly outstanding, and the two scholars with the highest publication volume (Fan Jia and Zhou Jian) also originate from this institution. Fudan University can be considered representative of the TME in HCC.

Through the analysis of high-frequency keywords, we have summarized four hotspot directions in the field of the TME in HCC: (1) the main components and roles in the TME; (2) immunotherapy; (3) combination therapy; and (4) the microenvironmental landscape.

Through keyword analysis of the TME in HCC, we found that the keyword “cell death” has seen a spike in citations over the last three years, and related keywords such as “ferroptosis”, “biomarker” and “diagnostic signature” have also emerged relatively recently, thus indicating that these research directions are becoming increasingly popular. Combined with the current research hotspots, we speculate that the effect of ferroptosis on TME in HCC may become a future research trend.

Increasing evidence indicates that the activation of ferroptosis may effectively inhibit the growth of HCC cells (66). Several studies have constructed prognostic signature models for HCC based on ferroptosis-related long noncoding RNAs or genes, which can predict tumor heterogeneity, immunotherapy response, immune suppression status, and other characteristics (67–70). Furthermore, scholars have elucidated the relationship between immune cells and ferroptosis, and there are many underlying mechanisms. Changes in these mechanisms can significantly affect innate immunity and adaptive immunity (71, 72), which seems to indicate that ferroptosis is closely related to the TME.

In recent years, studies have shown that the inhibition of APOC1 can reverse the transformation of M2 TAMs to M1 TAMs through the ferroptosis pathway, thereby inhibiting the development of HCC (73). In addition, the inhibitor iFSP1 of ferroptosis suppressor protein 1 can not only induce ferroptosis in HCC but also increase the infiltration of immune cells such as M1 macrophages, dendritic cells, and CD8+ T cells in tumors (74). This means that ferroptosis can synergize with anti-tumor immune responses. However, ferroptosis seems to have an antagonistic effect on the anti-tumor immune response. The anti-tumor effects of immune cells are affected by ferroptosis, thus leading to a decrease in anti-tumor activity, and ferroptosis can also trigger the infiltration of immunosuppressive cells into tumors (75–77). Therefore, an exploration of the mechanism of ferroptosis in the TME and the identification of candidate genes and pathways that can induce ferroptosis in HCC while preserving anti-tumor immune cell function may be the focus of subsequent research.

In conclusion, ferroptosis is closely related to the TME and has synergistic and antagonistic effects on anti-tumor immune responses in HCC. These two effects seem contradictory, but they are very common and reasonable in the process of biological development. The reason for this effect may be that the mechanism of ferroptosis in the TME is not clear. Therefore, it is necessary to understand the mechanism of ferroptosis in the TME of HCC, and on this basis to explore new diagnostic biomarkers and effective therapeutic targets, which may be a potential therapeutic strategy.