The tumor microenvironment (TME) surrounds tumor cells and consists of fibroblasts, immune cells, blood vessels, extracellular matrix (ECM) components, and a range of signaling molecule types (1, 2). Many studies have documented close relationships between tumors and the TME that dynamically shape tumor growth and development through the control of the secretion of bioactive molecules that can facilitate angiogenesis and immune evasion. Different immune cell types within the TME can also shape the tumor progression, especially in patients with confirmed triple-negative breast cancer (TNBC) (3–5).

TNBC cases account for 10-20% of all breast cancer diagnoses, and these tumors exhibit pronounced heterogeneity (6). The immune microenvironment associated with these tumors includes the expression of high levels of vascular endothelial growth factor and other molecules conducive to tumor growth and invasivity, together with abundant tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs) that play dual roles in driving and restraining TNBC development and progression (7). Efforts to understand the TME associated with TNBC tumors have the potential to aid in the diagnosis, prognostic evaluation, and therapeutic management of this form of cancer. Tumor-associated cells also undergo dynamic changes over the course of tumor progression and metastasis such that the intratumoral and peritumoral landscapes are dynamic and unique for each patient. Several different pathways have been identified whereby the TME can promote or suppress TNBC progression through heterogeneity and plasticity (8–10). There is thus a clear need for qualitative analyses of current research focused on the TME within TNBC to highlight active and future hotspots for scientific investigation.

Bibliometrics, an interdisciplinary science, equips researchers with mathematical and statistical tools for a comprehensive and objective evaluation of a specified research field (11, 12). This analytical approach facilitates a deeper understanding of the evolution and development of specific research trajectories. As it enables a comparative study of contributions from diverse countries, organizations, experts, and publications, it also describes and forecasts the future trajectory of a research topic (13). Bibliometric analysis has been used in various fields of medicine, such as cardiovascular diseases (14), endocrine diseases (14), gastrointestinal tumors (15), and the immune microenvironment (16), and is becoming increasingly important in assessing hot frontiers and formulating guidelines between TME and TNBC.

Here, this study explores the hotspots and frontier trends of TME in TNBC research from 2005 to 2023, and forms corresponding knowledge maps with CiteSpace and VOSviewer. This study provides the latest progress, evolution paths, frontier research hotspots, and future research trends for TME-related research in the basic research and clinical prevention and treatment of TNBC.

The TME consists of ECM components and a range of cell types that surround tumor cells, including fibroblasts, endothelial cells, stromal cells, and both innate and adaptive immune cell types. The diverse composition of the TME yields a dynamic and complex network that influences interactions between immune cells and TNBC cells (19). There have been many important research advances focused on the TME in TNBC and other cancer types, and it remains an area of active scientific interest (2, 20). Here, public databases were queried to extract data pertaining to studies focused on the TME in TNBC, after which a bibliometric assessment was performed for pinpointing associated research niches. Such resultant data highlight the key importance of the TME in TNBC.

Analyses of total citation output from specific countries can provide insight into academic status for a specific country within a particular research niche. To date, the USA predominates in research impact concerning TME and TNBC, with 623 publications and 18,951 citations, followed by China (465 publications; 7,498 citations), Italy (106; 3,984), Japan (92; 2,884), and Germany (70; 2,119). Even though the USA remains currently predominant in this field, research output from China continues to grow in both study quality and overall study output such that it will likely surpass the USA within coming years. Indeed, more studies were published in this research space from China than from the USA in 2022 (162 vs.104).

There has been a persistent rising trend in article numbers within such a niche since this topic emerged in 2005. Especially in recent years, the volume of publications has surged, which may be attributed to the technological innovations in this field, such as single-cell sequencing (21). This new appreciation of the biology of TNBC has already led to the development of novel targeted agents, including PARP inhibitors, antibody-drug conjugates and immune-checkpoint inhibitors, which are revolutionizing the therapeutic landscape and providing new opportunities both for patients with early-stage TNBC and for those with advanced-stage disease (22). The countries that first published research in this field were Canada and the USA in 2005 and 2007, respectively. Authors in the USA have published 623 total articles, with 18,951 citations, an H-index of 72, and a citation/article ratio of 30.42, which exceed values of other countries. In contrast, China and Italy, which began publishing research on this topic in 2014, ranked second and third, respectively, in total publication numbers, and exhibited relatively low H-indexes (43 and 29) and citation/article ratios (16.12 and 27.23). While the total research output from China to date in this space is composed of 465 articles with 7,498 citations and both H-index and citation/article ratio values below those for the USA, as of 2022 the annual publication volume from China has surpassed that of the USA, emphasizing the need to pay careful attention to the research momentum of Chinese authors ( Figure 2B , Table 1 ).

The journals that have published the highest numbers of studies related to the TME in TNBC to date include Cancers, Frontiers in Oncology, International Journal of Molecular Sciences, Breast Cancer Research, and Frontiers in Immunology. Of these journals, Cancers peaked in the number of published articles, followed closely by Frontiers in Oncology, together with all top-10 journals were similar in terms of output volume. When assessing IF values, 8 of the top 10 publications with peak impact were published within the previous five years, whereby the topIF value was exhibited by Nature Medicine (IF = 87.241, JCR = Q1). Nature Medicine could therefore represent a main source of research breakthroughs pertaining to the TME in TNBC within the near future.

The top 10 most productive research institutions in this field were largely consistent with the 10 most productive countries for research output, emphasizing the central role that these institutions serve as facilitators of high-quality academic output. These institutes are expected to produce further breakthroughs relating to the role of the TME in TNBC within coming years. A co-authorship analysis was additionally performed to explore relationships among nations, institutions, and authors, with greater linkage strength suggestive of more robust collaborative interactions. In cluster analyses, the most highly represented institutions included the Chinese Academy of Sciences, Johns Hopkins University, Dana-Farber Cancer Institute, The Netherlands Cancer Institute, University at Buffalo-SUNY, University of Texas MD Anderson Cancer Center, and Weill Cornell Medicine. However, the limited nature of collaborations among these universities highlights the importance of establishing robust relationships that can drive more advanced research in this field in coming years.

The volume of published studies associated with particular topics and categories can provide insight into the major hotspots and areas of research focus in a particular field. The 14 top categories related to the TME in TNBC appeared over 50 times among identified studies, emphasizing growing interest in drugs, immunology, and materials development in this space. The first nanoscience and nanotechnology-related article published in this field, titled “Caging Cancer”, was published in Nanomedicine - Nanotechnology Biology and Medicine. This article served as a general overview of cancer-related topics presented for consumption by a general audience, emphasizing the need to treat patients by effectively addressing many different tumor-related factors through appropriately tailored therapeutic strategies in a sequential or simultaneous manner. The chemotherapeutic drugs currently used to treat patients exhibit a high degree of cytotoxicity and only target a single major cancer-related pathway. Nanomedicine-based strategies, in contrast, offer the opportunity to combine multiple therapeutic strategies in a single nanodevice of high complexity. At present, the promise of nanomedicines remains relatively underappreciated, as evidenced by the untapped potential of the gadolinium fullerenol cage molecule Gd@C-82(OH)22. Researchers have demonstrated that this nanomedicine is largely nontoxic and targets multiple tumor-related pathways at the same time, effectively arresting tumor growth even when used to target TNBC cells. These results suggest that developing a more in-depth understanding of the relationships between the physicochemical properties of nanomedicines and biological outcomes in a therapeutic setting may ultimately facilitate the advent of a new approach to reliably treating cancer (20). The first immunity-related article identified in this analysis was published in 2013 in the journal OncoImmunology and was entitled “Tumor-infiltrating lymphocytes, breast cancer subtypes and efficacy” (23). This article consisted of an in-depth analysis of over 2000 patient samples derived from a randomized clinical trial, and it ultimately identified a close relationship between high levels of TILs and excellent prognostic outcomes in TNBC patients. In HER2-overexpressing patients, these cells also correlated with better clinical responses to immunogenic chemotherapy, suggesting that immunomodulatory therapeutics may provide a novel avenue for the treatment of patients with aggressive forms of breast cancer (23). In more recent years, a high number of studies focused on this research space such that immune- and material-related therapies are predicted to remain an important focus of active exploration in the future. Multidisciplinary scientific development and ongoing optimization efforts focused on drug efficacy will also inevitably continue over time.

Co-occurrence analyses were also performed with the goal of identifying key topics of research in this field as a means of aiding researchers navigating through various studies. Using keywords derived from study titles and abstracts, a co-occurrence network was established that included three major clusters pertaining to clinically important therapy-/mechanistic-linked studies. Keywords exhibiting the greatest centrality and weight in this network (metastasis, tumor-infiltrating lymphocytes, immunotherapy, chemotherapy, PD-L1, nanoparticles, resistance, and subtypes) are expected to correspond to research niches within this theme, underscoring requirements pertaining to further TNBC-focused research concerning such niches, linked with avenues of investigation. For instance, in recent years, a growing understanding of the molecular mechanisms underlying resistance to taxanes, androgen receptor signaling inhibitors (ARSIs), and poly(ADP-ribose) polymerase inhibitors (PARPi) has emerged. Consequently, strategies to overcome resistance to these therapeutic agents have been developed, significantly enhancing drug efficacy (24). These advancements have notably contributed to the treatment of TNBC.

With the exception of the utilized colors, generated visualization maps appeared identical to the prepared co-occurrence maps, coloring nodes in accordance with mean year of publication for each keyword. Within this analysis, certain keywords exhibited coloration consistent with a greater research focus in recent years (pembrolizumab, immunotherapy, TILs, nanoparticles, combination, and biomarker), indicating that they may be key areas of active research worthy of additional study for researchers seeking to design novel therapeutic approaches targeting the TME in TNBC. Nanotechnology has emerged as a cornerstone in the modulation of the TME, catalyzing the advancement of innovative therapeutic approaches for TNBC. A spectrum of nanoparticles, including silver, gold, and platinum, have been actively incorporated into the treatment modalities for TNBC. State-of-the-art nanoparticle synthesis has been achieved via an array of methodologies, spanning chemical, physical, electrochemical, and biosynthetic techniques. Importantly, the synergy between traditional plant-derived chemotherapeutic agents and engineered nanoparticles has yielded profound anti-cancer properties. These collaborations have been recognized for their environmental sustainability, cost-effectiveness, and enhanced biological efficacy (25). Collectively, these strategies represent promising avenues for the design of novel interventions targeting the TME within the context of TNBC.

The present bibliometric assessment, to the authors’ knowledge, reflects a pioneering focus on research trends pertaining to the TME in TNBC patients. While these results provide a comprehensive high-level overview of research findings in this space with corresponding visualizations of related publications, they are subject to some limitations. For one, the investigation utilized WoS SCIE and excluded any studies not published in English. The significance of more recently published investigations could have been disregarded within a degree as they will inevitably exhibit lower citation frequencies shortly after publication. As bibliometric trends change over time, the conclusions of this study may similarly be altered. Future bibliometric analyses not restricted to English language studies may be warranted in the future.

Together, the present data provide insight into research trends throughout the globe related to research focused on the TME in TNBC. At present, the USA is the predominant contributor to this research niche, and peaking in related studies were published within Cancers journal. Clinical studies focused on targeting the TME in this cancer type are potentially a valuable sphere for future research focus, together with present research niches involving studies related to metastasis, tumor-infiltrating lymphocytes, immunotherapy, nanoparticles, chemotherapy, and angiogenesis.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

PL: Writing – original draft. JL: Validation, Writing – original draft. XT: Investigation, Resources, Writing – original draft. ZX: Visualization, Writing – original draft. WD: Data curation, Writing – original draft. CZ: Data curation, Writing – original draft. WW: Writing – review & editing. JZ: Writing – review & editing.