Research trends on lactate in cancer: a bibliometric analysis and comprehensive review (2015–2024)

An extensive search and analysis were conducted using the Web of Science Core Collection (WoSCC) database. The Web of Science (WoS) is one of the world’s largest and most comprehensive academic information platforms, encompassing over 9,000 academic journals across diverse scientific disciplines (22). The WoS database is globally recognized as a comprehensive repository of authoritative and influential academic journals. Therefore, the WoS Core Collection databases, including the Social Science Citation Index (SSCI) and Science Citation Index Expanded (SCIE), were selected as the data source for this study. Subject searches conducted in the Web of Science Core Collection (WoSCC) (Supplementary Material). After reviewing the relevant literature and excluding articles that were not pertinent to this study, a total of 5,999 articles were included for analysis. The retrieved data were collected on February 20, 2025, to minimize bias caused by daily updates. The search results were exported as ‘complete records and references,’ including titles, authors, institutions, abstracts, journals, publication dates, and other information. These were saved as a plain text file (download_.txt) and imported into VOSviewer software to check for duplicates.

In the Web of Science (WoS) database, The University of Texas MD Anderson Cancer Center (UT MDACC) is indexed as an independent institution distinct from The University of Texas. To maintain consistency with the original data structure and ensure reproducibility, we retained this classification. Notably, UT MDACC operates both as a degree-granting academic unit of The University of Texas System and as a standalone cancer research entity, which may explain its separate designation in bibliometric databases.

In this study, we utilized CiteSpace, VOSviewer, and RStudio’s bibliometric package for literature visualization and analysis, Microsoft 365 for table creation, Scimago Graphica for country mapping, and PowerPoint to design a flowchart of the literature screening process. CiteSpace, developed by Professor Chaomei Chen from Drexel University, is a free Java-based application designed for the visual analysis of trends and patterns in scientific literature (23). VOSviewer, developed by the CWTS Center at Leiden University in the Netherlands, offers robust functionality and a practical interface for co-occurrence and co-citation analyses (24). The number of publications, the average citations per publication, and the H-index were extracted from the Web of Science citation reports. The H-index, originally developed to measure a researcher’s scientific output, is based on the number of publications (N) that have been cited at least N times (25).

This study included 5,999 relevant publications from WoSCC between 2015 and 2024. As of February 20, 2025, the included papers have garnered 144,775 citations, averaging 24.13 per paper, and collectively achieved 135 H-indices, according to the WOS citation report. The temporal distribution of publications exhibits a generally upward trend over the 10-year period, for citation volume 2014–2018 steady accumulation, the first citation inflection point occurs in 2019 and peaks in 2022. after 2023 the growth rate of issue volume slows down, but citation volume remains high (Figure 2).

Over the past 10 years, research articles focusing on lactic acid and cancer have been published across 108 countries/regions. China leads with 2,840 publications, followed by the United States (1,149), Germany (315), Japan (279), Italy (251), South Korea (244), England (224), India (195), France (158), and Brazil (128). In terms of citation counts, China is at the forefront with 62,840 citations, followed by the United States (46,181), Germany (8,691), England (7,493), and South Korea (7,091). Ranked by average citation count, the top countries are the United States (40.19), followed by England (33.45), France (29.92), South Korea (29.06), and Germany (27.59) (Table 1). Based on the SCImago Graphica Beta 1.0.26 analysis, the United States emerges as the most active participant in international collaborations, primarily partnering with China and Germany. Notably, the collaboration between China and the United States is the most extensive (Figure 3).

Table 5 lists the 10 most cited articles, with the highest citation count belonging to Zhang D ‘s study on Metabolic regulation of gene expression by histone lactylation. This study, published in 2019 in Nature, a highly prestigious and widely influential journal, for the first time, it was revealed that lactate directly catalyzes histone lysine lactylation (H3K18la), regulates gene expression and was demonstrated in macrophages that lactylation modifications drive M2-type polarization and promote cancer immunosuppression in a high-lactate microenvironment. The top 10 most cited articles investigate the crucial roles of lactic acid, in tumor development from diverse perspectives. These studies highlight the significant impact of lactic acid on tumor biology and elucidate the complexity of the associated metabolic networks.

In this study, VOSviewer was employed to conduct a keyword co-occurrence analysis, thereby illustrating the distribution and characteristics of current research hotspots in the field of lactic acid and cancer. Themes were identified through keyword co-occurrence analysis using VOSviewer (v1.6.18), which automatically clustered high-frequency keywords (occurrence ≥68) into five distinct groups based on association strength. Each cluster’s thematic label was derived by manually evaluating its core keywords for conceptual coherence.

A labeled visualization of keyword co-occurrences in lactate and cancer research was then generated (Figure 4) to identify research hotspots and core content. The keywords ‘cancer,’ ‘expression,’ and ‘metabolism’ emerge as the most prominent, suggesting that a substantial body of research is concentrated around these themes. The keywords included can be classified into the following six categories (Table 6, Figure 5): (1) Metabolic-epigenetic coaxial effects; (2) Tumor microenvironment-immunosuppressive network; (3) Innovative cancer therapy and drug delivery systems; (4) Lactate-mediated signaling cascades; (5) Metabolically Targeted Therapeutic Strategies, it can be concluded that the keywords ‘lung adenocarcinoma’, ‘tumor microenvironment’, ‘blockade’, and ‘chemodynamic therapy’ are key words that have appeared in the last three years (Figure 4). Based on the trend analysis of topics over the past 10 years (Figure 6), “lactylation”, “ferroptosis”, “immunotherapy”, “ lactate metabolism” and ‘breast cancer’ are terms that have grown significantly beyond 2019, suggesting that research on metabolic reprogramming in cancer is gaining interest, especially in lactate and related pathways; Terms such as “drug delivery” and “chemotherapy” also show steady growth, reflecting the continued efforts of researchers to refine and develop novel therapeutic strategies, it may also mean that more and more research is focused on personalized or targeted cancer therapies; “polymeric micelles” and “nanoparticles” have become increasingly popular in recent years, suggesting that researchers are More advanced drug delivery systems are being explored to improve drug efficacy or minimize side effects. Through the analysis of burst keywords, keyword clustering, and topic trends, it is possible to evaluate both past research focal points and predict future research directions in this field.

The joint analysis of countries, institutions, and keywords (Figure 7) clearly demonstrates the dominant role of China and the United States in lactate and cancer research, as evidenced by the prominence of core keywords and key institutions. The keywords ‘glycolysis’, ‘lactate’ and ‘Warburg effect’ serve as central hubs in this field of study, with relevance extending across multiple countries and institutions. Chinese institutions, including Shanghai Jiaotong University, Fudan University, Nanjing Medical University, Chinese Academy of Sciences, Sun Yat-sen University, Zhejiang University and Central South University have concentrated their research efforts on elucidating the underlying mechanisms associated with keywords such as ‘glycolysis,’ ‘Warburg effect,’ ‘lactate,’ and related terms. Institutions in the United States, such as the University of Texas System, the University of California System, and Utmd Anderson Cancer Center exhibit a well-balanced approach to research that integrates metabolic studies with clinical applications. Their investigative scope is notably broad, addressing a diverse array of topics that include ‘metabolism’ ‘cancer’ and ‘breast cancer.’ Researchers from other countries tend to focus on more specialized research pathways, highlighting terms like “aerobic glycolysis” and “metabolism” in their studies.

From 2015 to 2024, the number of publications exhibited an overall upward trend and can be segmented into two distinct phases. The first phase is from 2015 to 2019, during which time the number of communications shows an increasing trend year by year. The significant growth, particularly from 2020 onward, indicates an increasing interest in this research area, likely driven by key advancements, including breakthroughs in lactate metabolism and tumor microenvironment mechanisms (26–32). In the second phase, from 2020 to 2024, the number of publications has stabilized at approximately 650, reflecting sustained research productivity in the field. Growth in the number of articles published in 2020 may be attributed to emerging hotspots in cancer metabolism research and significant technological advancements, including multi-omics approaches and metabolic targeting therapies (33, 34). Regarding the citation trend, citations grew rapidly from 2015 onward, peaking in 2024. This indicates that earlier research findings were extensively acknowledged and highly cited in subsequent studies.

As evidenced by the number of publications, citation counts, and average citations per country, China leads in publication volume. In contrast, the United States exhibits higher average citations per article, suggesting greater research influence, quality, and international recognition. Germany, England, and South Korea follow with the next highest numbers of publications and citations, indicating their mid-tier global standing and demonstrating steady growth in both research output and impact. The United States and China stand at the epicenter of international research collaboration, boasting the most extensive and densely interconnected cooperative networks, particularly between the two nations. Furthermore, the United States maintains close collaborative ties with notable European nations such as Germany and England. The United States has a wide range of collaborations across the globe, demonstrating that the strong combination of the United States and China is an important driver of development in the field, as well as the participation and contributions of other countries.

Among the top 10 academic institutions with the highest publication output in the field of lactate and cancer, eight are based in China, highlighting the country’s leadership in scientific productivity. The remaining two institutions are located in the United States. In addition, the institution with the most publications is the University of California System, which focuses on several key areas of research related to lactate, including: lactate-related epigenetic regulation (35), the relationship between the TCA cycle and lactate (36, 37) and metabolic adaptation of the immune microenvironment (38–40). Shanghai Jiaotong University, while being a secondary contributor in terms of publication volume, focuses on the relationship between lactate metabolism and tumor development, treatment and related mechanisms in lactate and cancer research, such as lactate metabolism and tumor mechanisms (41–44), Lactic acid and tumor therapy (45–48), Lactic acid and immunologic and chemotherapeutic sensitivity (49–52). Moreover, the organization has also conducted studies on lactic acid in different types of cancer, hepatocellular carcinoma (53, 54), pancreatic cancer (55, 56), breast cancer (57), lung cancer (58, 59).

Kurhanewicz, John, and Vigneron, Daniel B. formed a closely collaborating author cluster whose research focuses on evaluating the role of lactate metabolism in various tumor types using Hyperpolarized ¹³C MRSI technology. Their 2015 article in NMR in Biomedicine, titled Real-time measurement of hyperpolarized lactate production and efflux as a biomarker of tumor aggressiveness in an MR-compatible 3D cell culture bioreactor (60) has been cited 41 times. This journal is an international academic publication dedicated to the application of Nuclear Magnetic Resonance (NMR) technology in the biomedical field, with an impact factor of 2.7.

The most cited article, Metabolic regulation of gene expression by histone lactylation, highlights that lactate directly catalyzes histone lysine lactylation (H3K18la), regulates gene expression and was demonstrated in macrophages that lactylation modifications drive M2-type polarization and promote cancer immunosuppression in a high-lactate microenvironment. An analysis of the 10 most cited articles over the past 10 years highlights the pivotal role of lactate in tumor biology and its integration into complex metabolic networks, offering new insights into tumor metabolism.

Keywords can help researchers identify emerging trends and grasp the direction of their research. The three most frequently occurring keywords were ‘cancer’, ‘expression’ and ‘metabolism’ indicating a primary focus on the role of lactic acid in cancer progression, epigenetic modifications, and tumor microenvironment regulation. An analysis of keyword relationships allows for their classification into four main categories: (1) Metabolic-epigenetic coaxial effects; (2) Tumor microenvironment-immunosuppressive network; (3) Innovative cancer therapy and drug delivery systems; (4) Lactate-mediated signaling cascades; (5) Metabolically Targeted Therapeutic Strategies. These clusters represent the primary focus areas of lactate and cancer research over the past 10 years.

Lactate, a central product of tumor metabolism, is intricately linked to the tumor microenvironment, including hypoxia, acidity, and immunosuppression, with metabolic reprogramming serving as a critical mechanism for microenvironmental regulation. For instance, lactic acid, a byproduct of cellular metabolism within the tumor microenvironment, facilitates cancer cell proliferation and invasion of the tumor microenvironment (61). In hypoxia-induced cancer cells, reduced LDHA expression leads to decreased LDHA activity, lactate production, and intracellular adenosine triphosphate (ATP) levels, significantly inhibiting colony formation and ultimately reducing cancer cell survival (62). Bok et al. also highlighted the dynamic nature of tumor metabolism by examining the role of lactate metabolism in prostate cancer metastasis (62). Moreover, tyrosine phosphorylation of PKM2 induces the Warburg effect (61), and phosphorylation of LDHA regulates redox metabolic homeostasis (63); both studies highlight the role of lactate in regulating the tumor microenvironment during metabolic reprogramming.

Lactic acid influences tumor progression during cancer invasion and metastasis by regulating extracellular matrix degradation and promoting cell migration, often resulting in increased treatment resistance and drug efficacy challenges. Studies have shown that lactic acid plays a key role in the signaling cascade mediating tumor progression. Research conducted by P. Jourdain et al. (64) revealed that L-lactate, generated through pyruvate metabolism, produces ATP and is released in an autocrine/paracrine manner. This process activates purinergic receptors and the PI3 kinase/P2Y/KATP signaling pathway, thereby counteracting glutamate-induced excitotoxicity and exerting neuroprotective effects. Additionally, lactate upregulates LDHB and MCT-1, converting lactate to pyruvate and generating ATP via the TCA cycle and oxidative phosphorylation (OxPhos), thereby driving tumor growth (65). In this study, the term pyruvate began to explode in 2016 and MCT-1 became a trending topic in 2019. However, lactic acid has also been shown to inhibit tumors. Zhang et al. (66) demonstrated that lactic acid creates a more acidic environment, favoring the selective conversion of α-ketoglutarate to L-2HG in tumors, which specifically induces tumor cell pyroptosis. The term metabolic reprogramming began to explode in 2021, lactic acid stimulates the secretion of IL-6 and VEGF by tumor-associated adipocytes through activation of GPR81, thereby further promoting tumor growth (67). Relevant studies suggest that targeting GPR81 and MCT-1 could offer a potential strategy for treating tumor malignancy (16–18).

Simultaneously, we analyze the frontiers, hotspots, and emerging trends in the research on lactic acid and cancer. Research on lactate and cancer focused on metabolic reprogramming and tumor microenvironment studies between 2015 and 2020. Since 2020, research has increasingly focused on functional mechanisms and clinical significance, with sustained growth in interest and relevance. In the past three years, keywords such as ‘metabolic reprogramming’, ‘polarization’, ‘lung adenocarcinoma’, ‘tumor microenvironment’, ‘blockade’ and ‘chemodynamic therapy’ reflect a shift in research focus from traditional metabolic mechanisms to metabolic intervention, immune microenvironment regulation (68–70), combination of new therapeutic techniques and applications in specific cancer types, such as lung adenocarcinoma (69, 71–73). In 2019, Zhang et al. (35) experimentally demonstrated that histone lysine lactylation (Kla), a novel in vivo post-translational modification, is derived from lactic acid. This modification represents a novel epigenetic mechanism linked to macrophage polarization, potentially affecting cancer progression and inflammatory disease pathways. Subsequently, terms such as polarization, metabolic reprogramming, and tumor microenvironment began to erupt in 2021. Although immune-related keywords have not appeared with significant frequency, the role of lactic acid in regulating immune cell function and the immune microenvironment is emerging as a prominent research focus. The synergistic effects of lactate with other metabolites and signaling pathways, such as Akt and HIF-1, in driving tumor progression are anticipated to become a prominent research trend. Furthermore, leveraging the metabolic properties of lactate to develop more targeted and efficacious therapeutic strategies may emerge as a promising trend in future research.

In contrast to the traditional approach of reviewing numerous studies to summarize the current state of research on the link between lactic acid and cancer, bibliometric analysis provides a more intuitive and efficient method for acquiring information in this field. Researchers can selectively access the information they need from the article, thereby enhancing the efficiency of scientific research, staying updated on the latest field hotspots, and identifying emerging topics. However, this study has several limitations. First, the literature analyzed was limited to the SCI-E and SSCI sections of the WoSCC database, which may restrict the data coverage. Although the WoSCC database is widely recognized for its rigorous assessment criteria and its extensive use in bibliometric research (74), important studies from other sources may still have been overlooked. Second, the inclusion of only English-language literature in this study may have resulted in the exclusion of high-quality, relevant studies in other languages. However, we supplemented our analysis with references cited in the publications.

The original contributions presented in the study are included in the article/. Further inquiries can be directed to the corresponding authors. 1