Structural and temporal dynamics analysis on immune response in low-dose radiation: History, research hotspots and emerging trends

Abstract

BACKGROUND

Radiotherapy (RT) is a cornerstone of cancer treatment. Compared with conventional high-dose radiation, low-dose radiation (LDR) causes less damage to normal tissues while potentially modulating immune responses and inhibiting tumor growth. LDR stimulates both innate and adaptive immunity, enhancing the activity of natural killer cells, dendritic cells, and T cells. However, the mechanisms underlying the effects of LDR on the immune system remain unclear.

AIM

To explore the history, research hotspots, and emerging trends in immune response to LDR literature over the past two decades.

METHODS

Publications on immune responses to LDR were retrieved from the Web of Science Core Collection. Bibliometric tools, including CiteSpace and HistCite, were used to identify historical features, active topics, and emerging trends in this field.

RESULTS

Analysis of 1244 publications over the past two decades revealed a significant surge in research on immune responses to LDR, particularly in the last decade. Key journals such as INR J Radiat Biol, Cancers, and Radiat Res published pivotal studies. Citation networks identified key studies by authors like Twyman-Saint Victor C (2015) and Vanpouille-Box C (2017). Keyword analysis revealed hotspots such as ipilimumab, stereotactic body RT, and targeted therapy, possibly identifying future research directions. Temporal variations in keyword clusters and alluvial flow maps illustrate the evolution of research themes over time.

CONCLUSION

This bibliometric analysis provides valuable insights into the evolution of studies on responses to LDR, highlights research trends, and identifies emerging areas for further investigation.

Key Words: Low-dose radiotherapy; Immune response; Immunotherapy; Bibliometric analysis; Radiation-induced immunogenicity; Synergistic therapies

Core Tip: This study provides a comprehensive bibliometric analysis of the immune response to low-dose radiotherapy (LDR) over the past two decades. It highlights key research trends, influential studies, and emerging hotspots such as ipilimumab and targeted therapy. Through structural and temporal dynamics, the analysis offers insights into global collaborations and the evolution of research themes, guiding future investigations in LDR. The findings are valuable for clinicians and researchers, helping to optimize therapeutic strategies and advance the field of radiotherapy.

INTRODUCTION

Radiotherapy (RT) is a key cancer treatment modality. Moderate (0.1-2.0 Gy) or high (> 2 Gy) doses of radiation can kill neoplastic cells and generate inflammation to stimulate anticancer immunity. However, these treatments can also damage normal tissues, impair immune functions[1,2], and increase the risk of secondary neoplasms[3-5]. In contrast, low-dose radiation (LDR) does not lead to these complications[6]. Furthermore, substantial evidence indicates that LDR inhibits the development of neoplasms in humans and experimental animals[7-10].

The documented effects of ionizing radiation on the immune system date back to early radiobiological studies following the discovery of X-rays[11,12]. Murphy JB was one of the first scientists to recognize the immunomodulatory effects of radiation and proposed that the effects-such as immune stimulation and tumor protection in mice-were dependent on factors such as the radiation dose, exposure volume, location, and the time interval between exposure and tumor challenge[13-15].

The effects of LDR on cancer immunotherapy have been extensively studied in recent decades[6]. LDR can stimulate both innate and adaptive immune responses. For example, it enhances the expansion and cytotoxicity of natural killer (NK) cells, activates dendritic cells, and augments T cell activation[16-18]. Additionally, LDR induces thymocyte apoptosis and promotes cell cycle progression in adaptive immune responses[19]. In vivo, LDR treatment protects human B lymphoblasts from high-dose radiation-induced (HDR) cell death[20]. Furthermore, LDR pretreatment can reduce HDR-induced DNA damage in human peripheral blood mononuclear cells[21].

In addition to oncology, LDR research has expanded to include its impact on autoimmune diseases, inflammatory responses, and infectious diseases, reflecting a broader appreciation of the interplay between LDR and various immune system functions[22-25]. These studies were primarily conducted before the development of antibiotics and anti-inflammatory drugs. Recently, with the emergence of the coronavirus disease 2019 (COVID-19) pandemic, LDR has attracted increasing attention as a potential strategy to mitigate COVID-19 mortality[26,27].

Bibliometric analysis has become a powerful method for assessing research trends and the impact of scientific publications[28-30]. This approach quantitatively evaluates various aspects of scholarly work, including publication output, citation patterns, and collaboration networks. In this study, we employed bibliometric techniques to: (1) Summarize the historical features of the literature on immune responses to LDR; (2) Highlight influential articles; (3) Identify active topics in the field; and (4) Reveal emerging trends for future research.

MATERIALS AND METHODS

Data acquisition and analysis

The research utilized the Web of Science Core Collection (WoSCC), which includes over 12000 reputable journals recognized by the global scholarly community. We retrieved all relevant articles from the WoSCC published between January 1, 2004, and November 20, 2023. The search strategy used was as follows: TS = (“low-dose radiotherapy” OR “low dose radiotherapy” OR “low-dose radiation” OR “low dose radiation”) AND TS = (“immune” OR “immuno”). The inclusion criteria for the literature were as follows: (1) Publications within the period from January 1, 2004, to November 20, 2023; (2) Articles in English; and (3) Document types limited to “article” and “review.” Two researchers (Wang SY and Wu JX) independently conducted the search and data extraction, with all searches performed on the same day to minimize bias from database updates. The collected data included title, author, institution, country, publication year, and keywords. Records were exported from the WoSCC as plain text files for further analysis. Ethical approval was waived by the local ethics board as the data were derived from publicly available databases, and no human or animal subjects were involved.

Bibliometric analysis instruments

CiteSpace: (1) Co-occurrence networks: CiteSpace was used to create and analyses co-occurrence networks, defined as simultaneous occurrences of authors, institutions, or countries in the same publication. Nodes and connections were colour-coded to distinguish publication years, with the node periphery colour indicating the year of initial linkage. The "tree rings" within nodes represent the frequency of co-occurrences over time. A red ring indicates a significant increase in citations during a given year, whereas a purple ring highlights centrality, linking disparate nodes in the network;

(2) Burst detection: Using Kleinberg’s method, CiteSpace was employed to detect thematic shifts over time, represented by citation bursts. These bursts identify periods of heightened scholarly interest in specific topics, keywords, or references, reflecting key moments when a topic is the focus of research;

And (3) Cluster analysis: CiteSpace algorithms were utilized to cluster publications on the basis of titles, abstracts, and keywords. This analysis generated a temporal map of research clusters and their evolution, revealing the trajectories of scientific exploration.

HistCite: HistCite Pro 2.1 was used to assess the citation impact of publications by calculating the local citation score (LCS) and the global citation score (GCS) within the WoSCC. By importing the dataset into HistCite, we identified the most influential studies on the basis of citation counts, highlighting the key publications that have shaped the field.

Alluvial diagram generation: To visualize the dynamic shifts in the research themes, we employed the alluvial generator tool. This tool provides a comprehensive view of the evolving research landscape by mapping keyword frequencies over time, illustrating the convergence and divergence of key themes within the field.

RESULTS

Historical features of the literature

Distribution of publications: Variations in the volume of scientific publications over time can serve as indicators of knowledge growth in a particular area of research, providing essential metrics to understand the field's evolution. A total of 1244 publications related to immunity and LDR were retrieved from January 1, 2004, to November 20, 2023. This dataset included 1000 research articles and 244 review articles, involving 8242 authors and 1905 institutions, published across 512 journals and 103 scientific categories (Table 1).

Table 1 Basic information on the distribution of the publications.

Categories	Publication	Articles	Review	Authors	Institutions	Journals	Subject categories
Amount	1244	1000	244	8242	1905	512	103

The annual research output is depicted in Figure 1A. From 2004 to 2013, the number of publications remained steady at approximately 30 papers per year. However, in the last decade, the publication volume has sharply increased, reflecting growing research interest and an expanding presence in the scientific community. This sustained growth highlights the field's evolving dynamics and increasing relevance in academic discourse. Figure 1B presents the top 20 journals, with INR J Radiat Biol leading in terms of publication volume, followed by Cancers and Radiat Res.

Figure 1 Distribution of publications. A: The annual distribution of publications; B: The number of articles from the top 20 journals.

Research landscape: The citation co-occurrence network in Figure 2 illustrates the foundational studies shaping the LDR and immunity landscape from 2004 to 2023. The network's colour gradient from white to red visually represents the historical progression of research, identifying pivotal studies through denser citation clusters. Notably, the works of Twyman-Saint Victor et al[31], Vanpouille-Box et al[32], Formenti et al[33], and Antonia et al[34] occupy prominent positions owing to their high cocitation frequency. Supplementary Table 1 provides a detailed list of the 30 most impactful papers, assessed by their citation traction both LCS and GCS. This dual analysis underscores the seminal works that drive the field forwards and highlights the interconnectedness of research within the broader academic conversation.

Figure 2 Citation co-occurrence network.

Scientific cooperation: Figure 3 illustrates strong scientific collaboration across countries, institutions, and authors. The United States leads in publication output, with significant collaborations with China, the United Kingdom, Italy, and France (Figure 3A). Institutional collaboration involves 516 institutions, with the University of Texas MD Anderson Cancer Center at the forefront, followed by the Chinese Academy of Sciences and the University of Sydney (Figure 3B). Further analysis reveals a preference for domestic collaborations over international partnerships, signalling the need for more global cooperation to reduce academic barriers. In the author collaboration network (Figure 3C), dense connections reflect substantial collaboration, particularly between researchers such as Nam Seon Young and Kim Ji Young, as well as Frey Benjamin, Fournier Claudia, Gaipl Udo S, Deloch Lisa, and Fietkau Rainer. He Kewen and Chen Dawei are also closely connected.

Figure 3 The scientific cooperation networks. A: Country collaboration; B: Institutional collaboration; C: Author collaboration.

Variation in the most active topics

Subject category burst: Figure 4 shows the top 30 subject categories with the strongest citation bursts from 2004 to 2023. The blue line represents the time interval, with bursts indicated by red line segments marking the beginning and end years. Emerging subject categories include physics, atomic, molecular & chemical engineering, biomedical otorhinolaryngology, materials science, biomaterials, geriatrics & gerontology, multidisciplinary science, nutrition & dietetics, pharmacology & pharmacy, neurosciences, and cell biology.

Figure 4 Top 40 subject categories with the strongest citation bursts.

Keywords burst: Keyword burst patterns were analysed to identify active topics in the fields of immune response and LDR over the past two decades. The top 50 keywords with the strongest burst strength are shown in Figure 5, highlighting current research hotspots and potential future directions. Notablybursts include "regulatory T cell" (2008-2017, burst strength: 11.62), "contact hypersensitivity" (2004-2010, burst strength: 8.8), and "non-Hodgkin’s lymphoma" (2005-2011, burst strength: 7.83). Special attention was given to keywords with bursts extending into 2023, as these may represent emerging research areas, such as ipilimumab, open label, multicentre, stereotactic body RT, squamous cell carcinoma, macrophage, resistance, and targeted therapy.

Figure 5 Top 30 keywords with the strongest citation bursts.

Reference bursts: Supplementary Figure 1 displays the top 30 references with the most citation bursts between 2004 and 2023. Kojima et al[35] had the first citation burst, sparking significant interest with a burst strength of 5.81. This study examined the relationship between glutathione levels and NK activity in mouse splenocytes following low-dose γ-rays. The strongest burst occurred between 2016 and 2020 with Twyman-Saint Victor et al[31] (burst strength: 13.28). This study revealed that combining radiation therapy with dual checkpoint blockade activated distinct immune mechanisms, increasing the efficacy of cancer treatment efficacy. Supplementary Table 2 lists all burst articles from 2004 to 2023, which are key for clinical and basic research professionals monitoring pivotal publications in LDR combined with immunity.

Emerging trends and new developments

Temporal variation of keyword clusters: Keywords were grouped into clusters on the basis of their relatedness, providing insight into evolving subfields within LDR and immunity research. The 20-year period was divided into four five-year phases, and the keyword clusters in each phase are shown in Figure 6. The first snapshot (2004-2008) revealed 8 clusters, including 0 "male zooid", 1 "stem cell transplantation", and 2 "contact hypersensitivity" (Figure 6A). The second snapshot (2009-2013) revealed 9 clusters, such as 0 "microarray", 1 "rituximab", and 2 "immune system" (Figure 6B). The third snapshot (2014-2018) identified 7 clusters, including 0 "gamma radiation", 1 "tumour", and 2 "low-dose radiotherapy" (Figure 6C). The fourth snapshot (2019-2023) revealed 8 clusters, including 0 "adaptive response", 1 "lung cancer", and 2 "expression" (Figure 6D). These evolving keyword clusters reflect the field’s shifting focus towards therapeutic outcomes and synergistic treatment approaches.

Figure 6 Keyword clusters snapshots across four periods. A: 2003–2007; B: 2008-2012; C: 2013-2017; D: 2018-2023.

Keyword alluvial flow visualization: The alluvial flow map (Figure 7) traces the dynamic landscape of research from 2004 to 2023, highlighting the emergence and interconnection of various themes over time. In 2023, the field is characterized by six prominent modules (Figure 8), which represent focal points. Module 1, “In-vivo” (Figure 8A), marks a shift toward systemic studies. Module 2, “Diagnosis” (Figure 8B), reflects advancements in detecting radiation-induced immune responses. Module 3, “Blockade” (Figure 8C), underscores innovations in immunomodulatory treatments. Module 4, “Bystander” (Figure 8D), explores the indirect effects of radiation. Module 5, “Current-thoracic-RT” (Figure 8E), focuses on specialized applications, and Module 6, “Double-blind” (Figure 8F), emphasizes the gold standard for clinical trial design. This visualization illustrates the field’s progression from foundational research to multidimensional inquiry, advancing patient-centred therapeutic strategies.

Figure 7 Keywords alluvial map (2004-2023).

Figure 8 Top 6 modules in 2023. A: Module 1; B: Module 2; C: Module 3; D: Module 4; E: Module 5; F: Module 6.

Timeline visualization of references: The reference cluster map (Figure 9) provides an intricate view of citation dynamics over the past two decades. Figure 9A shows a timeline visualization of citations across the study period, offering a longitudinal perspective on research impact. Certain classical papers have played essential roles in advancing the field (Figure 9B). For example, Vanpouille-Box et al[32], belonging to cluster 0 with a cocitation frequency of 51, demonstrated that the DNA exonuclease Trex1 regulates the immunogenicity of tumors induced by RT. This study identified Trex1 as a potential target for enhancing RT efficacy in cancer treatment. Antonia et al[34], with a co-occurrence frequency of 42, reported that durvalumab use after chemoradiotherapy significantly improved overall survival in patients with Stage III non-small cell lung cancer, emphasizing the potential of immunotherapy in this setting. Klug et al[36] showed that low-dose irradiation induces macrophage differentiation into the iNOS⁺/M1 phenotype, facilitating effective T cell immunotherapy. Wunderlich et al[37] reported that low and moderate doses of ionizing radiation (up to 2 Gy) alter macrophage behaviour by modulating their migration and chemotaxis, promoting an anti-inflammatory cytokine environment. Venkatesulu et al[38] identified radiation-induced lymphopenia as a significant factor influencing survival outcomes in patients with solid tumours. Figure 9C shows the citation distribution of these key publications, illustrating their fluctuating influence over time.

Figure 9 Reference clusters map. A: Citation timeline visualization; B: Burst citations in clusters 0, 1, 2, 4, and 10; C: Citation frequency distribution of the burst citations.

DISCUSSION

Historical features and evolution

This large-scale bibliometric analysis reviewed the structural and temporal characteristics of publications in the field of immune response and LDR over the past two decades. Studies on the response of the immune system to LDR are still emerging, with a dramatic increase in the number of publications, extensive scientific collaborations, and a dense citation network.

The analysis reveals a significant rise in research related to immunity and LDR, especially in the last decade. This surge in interest highlights the growing impact and relevance of this field within the scientific community. Key journals such as INR J Radiat Biol, Cancers, and Radiat Res have been pivotal in disseminating research findings. Notably, studies by Twyman-Saint Victor C, Vanpouille-Box C, and Formenti SC have significantly influenced the direction of research on LDR and immunity. Scientific collaboration in this field has been robust, with the United States leading in research output and fostering partnerships with countries such as China, the United Kingdom, Italy, and France. These collaborative efforts reflect the global recognition of the importance of investigating the immunological effects of LDR.

Research hotspots and emerging trends

While active topics in LDR and immune response evolve over time, the most recent keyword bursts have the potential to become future research hotspots. These keywords reflect active explorations of immunotherapeutic strategies combined with LDR, such as immunotherapy drugs (e.g., ipilimumab), clinical research methodologies (e.g., open label, multicenter), RT techniques (e.g., stereotactic body RT), specific cancer types (e.g., squamous cell carcinoma), treatment resistance, patient outcomes, targeted therapies, and management strategies.

Moreover, the temporal variation of keyword clusters illustrates the evolution of research themes. Earlier studies were more foundational and focused on regulatory T cells, X-rays, and gamma radiation, providing essential insights into the biological interactions of radiation. In more recent years, research has shifted towards translational studies, as evidenced by the emergence of clusters related to immune checkpoint inhibitors, abscopal effects, and cancers such as lung cancer and glioma. These developments point to a more nuanced inquiry into therapeutic outcomes and synergistic treatment approaches. The emerging clusters suggest that researchers are exploring new technologies and strategies to improve clinical outcomes.

The reference cluster map offers a historical perspective on the impact of key publications in the field. Studies by Vanpouille-Box et al[32], Antonia et al[34], Klug et al[36], Wunderlich et al[37], and Venkatesulu et al[38] have significantly influenced the direction of research, covering critical aspects of the immunomodulatory effects of LDR, such as DNA exonuclease regulation, macrophage differentiation, and radiation-induced lymphopenia.

Implications and future directions

The findings from this bibliometric analysis shed light on the dynamic evolution of immunity and LDR research. This study serves as a valuable resource for researchers seeking to identify current hot topics and potential areas for future investigations. The temporal dynamics of immune responses to LDR involve a series of coordinated events, such as immune cell recruitment, activation, and differentiation, which are crucial for understanding how LDR modulates the immune system and influences tumor progression. Initially, innate immune cells such asmacrophages and dendritic cells respond to radiation by secreting proinflammatory cytokines, which recruit adaptive immune cells such as T and B lymphocytes[12,13]. Over time, these immune cells differentiate into effector and memory subsets, contributing to tumor suppression or immune tolerance[6,7]. Furthermore, LDR has been shown to influence macrophages, polarizing them towards an M1-like phenotype that enhances antitumor immunity[36]. The long-term effects of LDR on immune homeostasis remain complex, and the impact of different radiation doses and fractionation schedules on immune responses represents a critical area for future research. Gaining insights into how varying doses and treatment regimens affect immune responses is essential for optimizing LDR and its integration with immunotherapies.

Several promising avenues for future research emerge from this study. First, the synergistic effects between LDR and emerging immunotherapies warrant further exploration. Previous studies have shown promising results in this area[31,33,39], and investigating this combination could lead to improved treatment outcomes for cancer patients. Second, expanding research beyond oncology could be beneficial. The implications of LDR in autoimmune diseases, inflammatory responses, and infectious diseases have already been explored[40-42], underscoring the broad impact of LDR on the immune system and presenting opportunities for multidisciplinary research. Additionally, advanced technologies, such as single-cell RNA sequencing and high-throughput sequencing, have the potential to reveal the intricate immunological effects of LDR[30,36]. These tools enable more sophisticated analyses of immune responses and their broader health implications. Finally, elucidating the regulatory mechanisms by which LDR modulates the immune system is critical. Insights in this area will provide a theoretical foundation and clinical guidance for innovations in cancer therapy and other fields[23,43].

Limitations

While we have identified key areas of synergy, such as the potential of combining immunotherapy with LDR, a deeper understanding of immune cell signalling pathways and their interactions with irradiated tissues requires experimental validation. Techniques such as single-cell RNA sequencing, flow cytometry, and cytokine profiling are recommended for future research.

CONCLUSION

In conclusion, the bibliometric analysis conducted in this study provides a comprehensive overview of the evolution of immunity and LDR research. It offers valuable insights for researchers, policy-makers, and clinicians, guiding the future trajectory of this dynamic field. By identifying key research trends and emerging areas, this study contributes to advancing medical science and improving patient care.