Mapping research trends in esophageal cancer immunotherapy: A decade of thematic evolution and emerging priorities

ABSTRACT

Immunotherapy has become a pivotal therapy for various cancers, including esophageal cancer, showing promising potential in improving survival rates and enabling personalized care. However, significant challenges occur in identifying predictive biomarkers, refining combination therapies, and managing immunotherapy-related adverse effects. This bibliometric study analyzed publications related to the use of immunotherapy in esophageal cancer management over a 10-y period (January 1, 2015, to October 14, 2024), retrieved from the Web of Science Core Collection. Keyword co-occurrence and co-citation analyses were performed to identify key contributors, central themes, and influential publications. A total of 545 publications on esophageal cancer immunotherapy were included in the analysis. A sharp increase in publication volume was observed beginning in 2019, with a peak between 2021 and 2023. China emerged as the leading contributor, accounting for 67.7% of the total output, while Zhengzhou University produced the highest number of publications among all institutions. Prominent individual contributors included Ken Kato and Shen Lin. Research hotspots centered on PD-1/PD-L1 inhibitors, combination therapies, and tumor microenvironment modulation. Notably, a clear temporal evolution in research focus was observed, with early studies emphasizing specific immune checkpoint targets and agents (e.g., PD-1, Pembrolizumab, and CTLA-4), followed by a shift toward mechanistic investigations involving the tumor microenvironment, treatment resistance, and prognosis. This study provides a comprehensive view of immunotherapy in the management of esophageal cancer, offering direction for future research and valuable insights for clinical innovation.

Introduction

Esophageal cancer represents a highly aggressive malignancy and remains one of the leading causes of cancer-related mortality worldwide, with over 600,000 new cases and approximately 540,000 deaths reported annually.¹ The disease burden shows marked geographic disparity – Eastern Asia, particularly China, accounts for more than half of global cases and deaths, while relatively lower incidence is observed in North America and Europe.² The two main types are esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC predominates in East Asia and Africa and is associated with lifestyle choices, including smoking, alcohol consumption,³ frequent intake of hot beverages, and consumption of pickled foods.⁴ In contrast, EAC is more common in Western countries, associated with chronic gastroesophageal reflux disease, Barrett’s esophagus, and obesity.⁵ These associations have been consistently confirmed in recent large-scale epidemiological studies and contemporary reviews.⁶ These subtypes not only differ in epidemiologic distribution and etiologic factors but also in their genomic landscapes. ESCC is characterized by frequent alterations in TP53, SOX2 amplification, and NOTCH1 mutations, while EAC commonly exhibits mutations in TP53, ERBB2 (HER2), and KRAS.⁷ Despite advances in surgery,⁸ radiotherapy, and chemotherapy,⁹ these conventional treatments have limited efficacy in advanced-stage disease. High recurrence rates and poor prognosis have kept the global 5-y survival rate below 20%.¹⁰ Underscoring the urgent need for more effective therapeutic strategies.

Recently, immunotherapy has become a groundbreaking modality in cancer treatment, demonstrating immense potential.¹¹ Among the most extensively studied targets are the immune checkpoint proteins programmed death-1 (PD-1) and its ligand PD-L1 (programmed death-ligand 1). Under physiological conditions, PD-1, expressed on activated T cells, binds to PD-L1 on antigen-presenting cells to maintain immune homeostasis. However, tumor cells often overexpress PD-L1, which interacts with PD-1 on T cells to suppress their activity, facilitating immune evasion. Immune checkpoint inhibitors targeting this pathway have shown remarkable efficacy in restoring anti-tumor immune responses.¹² These inhibitors have driven significant advancements in treating various cancers.¹³ In the context of esophageal cancer, PD-1 inhibitors, such as Pembrolizumab, have gained approval for use in treating advanced disease, demonstrating considerable efficacy in clinical trials.¹⁴ Furthermore, other immunotherapeutic approaches, including T-cell therapies,¹⁵ and cancer vaccines¹⁶ are actively being explored and refined. These developments reflect a broader research trend shifting from monotherapies toward integrated, multi-modal approaches aimed at overcoming resistance and enhancing long-term treatment efficacy.

Despite the significant progress of immunotherapy in esophageal cancer, several challenges persist in its clinical application. These include low response rates, treatment relapse, and resistance,¹⁷ as well as the lack of effective biomarkers for predicting therapeutic efficacy.¹⁸ Additionally, optimizing combination therapies remains a pressing need. In recent years, research focus has gradually shifted from monotherapies targeting PD-1/PD-L1 to more integrative approaches, such as tumor microenvironment modulation, biomarker-guided treatment, and personalized immunotherapy combinations. These evolving trends underscore the need for a systematic overview of the field. Bibliometric analysis is a quantitative method for evaluating academic literature based on citation patterns, co-authorship networks, and keyword co-occurrence. It enables researchers to map scientific developments, identify influential contributors, and uncover emerging trends in a given field. Consequently, this study conducts a bibliometric analysis of global research, focusing on major themes and emerging trends in esophageal cancer immunotherapy. Utilizing bibliometric tools such as CiteSpace and VOSviewer, this study will provide a comprehensive analysis across multiple dimensions, including research trends, major contributors, hotspot analysis, and thematic evolution. The aim is to inform future investigations and foster the continued advancement of immunotherapy in the treatment of esophageal malignancies.

Materials and methods

Data used in this study were sourced from WOS Core Collection database, an influential academic citation resource globally and widely used in bibliometric research.¹⁹ The literature retrieval was conducted on October 14, 2024. The search strategy employed the following query: Topic Search (TS) = ((esophageal cancer OR esophagus cancer OR esophageal carcinoma OR esophagus carcinoma OR carcinoma of the esophagus OR esophageal tumor OR esophagus tumor) AND (Immunotherapy OR Immunotherapies OR immunotherapeutic)). The time range for the search spanned from January 1, 2015, to October 14, 2024, covering all relevant literature on esophageal cancer immunotherapy published in the past decade. This timeframe and strategy ensured that the data retrieved were both comprehensive and up to date. The inclusion criteria for the literature included the following: article type (research articles and reviews), English language, research topic related to esophageal cancer immunotherapy, and full-text availability. Exclusion criteria included retracted articles, unavailable full-text documents, non-English language articles, and studies that did not directly focus on esophageal cancer immunotherapy – such as those addressing other cancer types, basic immunological mechanisms without disease-specific application, or general immunotherapy reviews not focused on esophageal cancer – as determined through abstract review. All filtered literature was exported in plain text format, including complete records to ensure the completeness and accuracy of subsequent analyses (Figure 1).

Figure 1.

Flowchart depicting the article selection process.

Bibliometrics analysis was applied in this study to quantitatively evaluate global research on esophageal cancer immunotherapy, including publication trends, collaboration networks, citation relationships, and research hotspots. By integrating performance analysis and visual mapping techniques, this approach enables the systematic identification of key contributors, influential literature, and emerging research themes within the field.

After exporting all retrieved literature data, data deduplication was done using CiteSpace 6.3.R1 software to confirm record uniqueness and precision. Following data cleaning, further analysis was conducted using CiteSpace and VOSviewer 1.6.20, two widely recognized tools for bibliometric analysis.²⁰ In CiteSpace, the time slicing was set from 2015 to 2024 with 1-y intervals, and burst detection was applied to identify emerging keywords and references. In VOSviewer, full counting was used for analyses of authors, institutions, countries, and keywords, whereby each contributing entity was counted once per publication. Country-level contributions were determined based on author affiliation information recorded in the Web of Science address field, and publications involving international collaboration were assigned to all participating countries, regardless of author order. Institution-level contributions were calculated using the same affiliation-based approach, whereby each institution listed in a publication was counted once under a full counting scheme. No fractional counting was applied, and no additional normalization procedures for author names, institutional affiliations, or country information were performed beyond the default data standardization implemented within CiteSpace and VOSviewer based on the original Web of Science metadata. CiteSpace was utilized to identify burst terms and generate co-citation clusters within specified time slices, while, VOSviewer was employed to create visual maps of research topics, aiding in the identification and interpretation of emerging trends and key contributors in this area. For the co-occurrence analysis of keywords, a threshold of at least 30 occurrences was set to identify core themes with high frequency in the field. After manually filtering out general terms such as “esophageal cancer,” “immunotherapy,” and “cancer,” 39 keywords were retained to represent the central research hotspots. Annual publication and citation trends were extracted from Web of Science metadata using built-in statistical modules within CiteSpace and VOSviewer, based on publication year and citation count fields.

Results

Publication volume

This analysis includes 545 publications contributed by 3,621 researchers across 780 institutions in 41 countries or regions. These publications were spread across 192 journals, citing 15,462 references from 2,184 journals. Among these, 382 (70.09%) were research articles, while 163 (29.91%) were review articles.

Publication trend

From 2015 to 2024, research on immunotherapy for esophageal cancer has shown substantial growth, underscoring expanding interest and exploration in this area. In the initial phase (2015–2018), studies were sparse, with a low annual publication rate, indicating an exploratory stage in the field’s development. Starting in 2019, however, publication volume surged, reaching a peak between 2021 and 2023, signifying a phase of rapid advancement (Figure 2A). This trend aligns with the maturation of immunotherapy techniques and their expanding applications in oncology. The marked increase in global research interest underscores the promising potential of immunotherapy for esophageal cancer. Even in 2024, the publication volume remains robust, reflecting ongoing engagement and active research momentum in the field.

Figure 2.

Annual publication trends in esophageal cancer immunotherapy. (A) Overall annual number of publications from 2015 to 2024. (B) Country-specific publication trends for China, the USA, Japan, England, and Germany over the same period.

Major contributors

At the National Level, China led globally in publication volume, accounting for 369 publications (67.71%). Since 2018, China’s output has surged (Figure 2B), surpassing the U.S. and demonstrating a strong growth trajectory. This dominance is also evident in the global distribution of publications (Figure 3B). Other contributors, including Japan, the United Kingdom, and Germany, show stable, albeit smaller, growth, indicating consistent investment in this field. These countries are geographically dispersed across East Asia, Europe, and North America, highlighting the broad international engagement in esophageal cancer immunotherapy research (Figure 3B). In terms of impact, with an average of 32.64 citations per article, the Netherlands demonstrates significant research quality despite contributing only 11 publications (Table 1). Similarly, South Korea and France have strong citation averages of 29.70 and 29.71, respectively. In contrast, China, despite its high publication volume, has a lower average citation rate of 11.35.

Figure 3.

Global distribution and international collaboration of research on esophageal cancer immunotherapy. (A) International collaboration network among countries. Each node represents a country, with node size proportional to publication volume. Links between nodes indicate international co-authorship relationships, and link thickness reflects the strength of collaboration. (B) World map showing the global distribution of publication volume by country. Color intensity corresponds to the number of publications, with darker shades indicating higher research output.

Table 1.

The top 10 productive countries related to immunotherapy for esophageal cancer.

Rank	Country	Counts	Percentage (N/545)	Citation	Citation/publication
1	China	369	67.71%	4189	11.35
2	USA	95	17.43%	1729	18.20
3	Janpan	44	8.07%	1160	26.36
4	England	19	3.49%	385	20.26
5	Germany	19	3.49%	360	18.95
6	Canada	11	2.02%	213	19.36
7	Nertherland	11	2.02%	359	32.64
8	South Korea	10	1.83%	297	29.70
9	France	7	1.28%	208	29.71
10	Ireland	7	1.28%	85	12.14

In the international collaboration network (Figure 3A), China, the U.S., and Japan hold central roles. China’s extensive collaborations enhance its research influence globally, while the U.S., though producing fewer publications, strengthens its academic standing through frequent partnerships. These patterns underscore a collaboration structure characterized by high-output Asian countries and highly connected Western partners (Figure 3A).

Among the ten institutions with the highest publication output, nine are from China, underscoring the country’s strong presence in this field (Table 2). Zhengzhou University leads with 40 publications, highlighting its central role in esophageal cancer immunotherapy research. Japan’s National Cancer Center Hospital East, the only non-Chinese institution in the top 10, has a high average citation rate of 28 per article.

Table 2.

Top10 institutions published literature related to immunotherapy for esophageal cancer.

Rank	Institution	Country	Article counts	Total citations	Citation/article
1	Zhengzhou University	China	40	515	12.88
2	Sun Yat Sen University	China	34	436	12.82
3	Fujian Medical University	China	26	187	7.19
4	Sichuan University	China	22	480	21.82
5	The Chinese Academy of Medical Sciences and Peking Union Medical College	China	22	235	10.68
6	Fudan University	China	21	181	8.62
7	Shanghai Jiao Tong University	China	20	461	23.05
8	Nanjing Medical University	China	20	191	9.55
9	National Cancer Center Hospital East	Janpan	18	504	28.00
10	Heibei Medical University	China	17	147	8.65

Tables 3 and 4 present the leading journals in publication volume and citations. Frontiers in Immunology top the list with 43 articles, followed by Frontiers in Oncology with 36. While Future Oncology published only 10 articles, its high average citation rate (30.7) underscores its significant impact. Among highly cited journals, the Journal of Clinical Oncology leads with 2015 citations and an impact factor of 42.1. The New England Journal of Medicine and Lancet Oncology also stand out, with citation counts of 1053 and 1043, respectively, and top-tier impact factors, highlighting their instrumental role in advancing esophageal cancer immunotherapy research.

Table 3.

The top 10 productive journals related to immunotherapy for esophageal cancer.

Rank	Journal	Article counts	Citation	Citation/article	IF	Category
1	Frontiers in Immunology	43	369	8.58	5.7	Q1
2	Frontiers in Oncology	36	288	8.00	3.4	Q2
3	Cancers	20	117	5.85	4.5	Q3
4	Journal of Thoracic Disease	12	111	9.25	2.1	Q3
5	Journal of Gastrointestinal Oncology	11	165	15.00	2.1	Q3
6	Cancer Immunology, Immunotherapy	11	80	7.27	4.6	Q1
7	Thoracic Cancer	10	32	3.20	2.3	Q2
8	Immunotherapy	10	81	8.10	2.7	Q3
9	Future Oncology	10	307	30.70	3.2	Q2
10	Esophagus	10	133	13.30	2.2	Q3

Table 4.

The top 10 co-cited journals associated with immunotherapy for esophageal cancer.

Rank	Cited Journal	Citation	IF	Category
1	Journal of Clinical Oncology	2015	42.1	Q1
2	New England Journal of Medicine	1053	96.2	Q1
3	Lancet Oncology	1043	41.6	Q1
4	Annals of Oncology	760	56.7	Q1
5	Clinical Cancer Research	702	10	Q1
6	Lancet	701	98.4	Q1
7	Nature	483	50.5	Q1
8	Journal of Immunotherapy Cancer	442	10.3	Q1
9	CA-A Cancer Journal for Clinicians	418	503.1	Q1
10	Frontiers in Immunology	408	5.7	Q1

In Table 5, Ken Kato (Japan) ranks as the most prolific author with 15 publications and 426 citations, followed by China’s Shen Lin with 10 publications. Japanese authors Takashi Kojima and Toshihiko Doi, though publishing fewer papers, demonstrate high influence, with average citation rates of 37.89 and 42.25 per article, respectively.

Table 5.

Top 10 most prolific authors in the field of immunotherapy for esophageal cancer.

Rank	Authors	Country	Count	Citation	Citation/article
1	Ken Kato	Japan	15	426	28.40
2	Shen Lin	China	10	214	21.40
3	Takashi Kojima	Japan	9	341	37.89
4	Pang Qingsong	China	8	164	20.50
5	Zhang Wencheng	China	8	164	20.50
6	Toshihiko Doi	Japan	8	338	42.25
7	Wang Jun	China	8	216	27.00
8	Yang Yang	China	8	178	22.25
9	Wang Feng	China	8	72	9.00
10	Chen Qixun	China	8	106	13.25

Overall Observations, China leads in publication volume and institutional contributions, while Japan excels in research quality, with both countries playing pivotal roles in advancing esophageal cancer immunotherapy research.

Research hotspots and evolution of themes

Based on keyword co-occurrence analysis, a total of 39 high-frequency terms were identified after filtering, representing the central research hotspots. The keyword co-occurrence density map (Figure 4) highlights key areas of focus in current research. Prominent terms such as “immune checkpoint inhibitors,” “chemotherapy,” “survival rate” “programmed death-ligand 1 expression,” and “chemoradiotherapy,” occupy the central density area, signifying their importance. Additionally, terms like “nivolumab,” “pembrolizumab,” “combination therapy,” “radiotherapy,” and “prognosis” indicate a growing emphasis on combined treatment strategies and survival prognosis analysis in recent years.

Figure 4.

Keyword Density Map. Brighter colors indicate higher keyword frequency, reflecting greater research focus. The closer the spatial distance between keywords, the more frequently they co-occur in the literature.

The analysis of emerging keywords (Figure 5) reveals an evolution in research focus. Early burst terms were predominantly associated with specific immunotherapy targets and drugs, such as “PD-1,” “Pembrolizumab,” and “CTLA-4,” reflecting a period when research concentrated on advancing and applying immune checkpoint inhibitors. Over time, the focus shifted toward more in-depth mechanistic studies, with terms like “tumor microenvironment,” “resistance,” and “prognosis” emerging. This shift underscores the growing interest in understanding the molecular mechanisms underlying immunotherapy and its adaptive responses in various pathological contexts. More recently, keywords such as “biomarkers,” “combination therapy,” and “safety” have surfaced, highlighting the increasing emphasis on personalized treatment strategies and the combined use of immunotherapies.

Figure 5.

Burst keywords in articles related to esophageal cancer immunotherapy. A blue line indicates the timeline, and the intervals in which bursts were found are indicated by red sections on the blue timeline, indicating the start year, the end year, and the burst duration.

Identified research gaps

Based on the bibliometric analysis, several underexplored areas in esophageal cancer immunotherapy research were identified. First, certain topics, including combination immunotherapy strategies and tumor microenvironment-targeted therapies, appeared less frequently among the analyzed keywords, suggesting relatively lower research activity. Second, while China led in publication volume, other countries contributed minimally, indicating potential geographic gaps in research output. Third, the co-citation and journal analysis revealed that specific treatment modalities and emerging therapeutic targets had relatively fewer publications. These observations are directly derived from the analyzed publication and citation data, providing an objective overview of understudied areas in the field.

Citation analysis

Based on co-citation analysis, we identified key research topics and highly cited works related to esophageal cancer immunotherapy. The co-citation network and cluster map presented in Figure 6 illustrate several core themes, with “Immunology” (#1) and “Oncology” (#2) being the central pillars of research, emphasizing their crucial roles in advancing the field. Additionally, clusters such as “Pharmacology” (#3) and “Surgery” (#4) reflect the interdisciplinary nature of this research area.

Figure 6.

Co-Cited Cluster Map. Each node represents a co-cited document, with node size proportional to the document’s co-citation frequency. Distinct color regions signify different research themes or disciplinary fields. Lines between nodes indicate co-citation relationships, with thicker or more numerous lines representing stronger co-citation ties.

The analysis of co-citation frequencies revealed 12 major clusters, encompassing a broad spectrum from basic immune mechanisms to clinical applications. Table 6 presents 5 papers with highest citation counts, which have significantly contributed to advancing immunotherapy for esophageal cancer. For instance, the study by Kato et al.²¹ comparing Nivolumab with chemotherapy (cited 183 times) and Kojima et al.’s²² investigation into the efficacy of Pembrolizumab (cited 179 times) have laid foundational theoretical and practical frameworks that continue to shape subsequent research.

Table 6.

The top five co-cited references related to immunotherapy for esophageal cancer.

Rank	Title	Journal IF	First Author	Citation	Category
1	Nivolumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomized, open-label, phase 3 trial.	Lancet Oncology IF = 41.6	Ken Kato	183	Q1
2	Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer	Journal of Clinical Oncology IF = 42.1	Takashi Kojima	179	Q1
3	Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced esophageal cancer (KEYNOTE-590): a randomized, placebo-controlled, phase 3 study	Lancet IF = 98.4	Jong-Mu Sun	178	Q1
4	Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial	The Journal of the American Medical Association IF = 63.1	Huiyan Luo	117	Q1
5	Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma.	New England Journal of Medicine IF = 96.2	Yuichiro Doki	113	Q1

Discussion

This bibliometric analysis offers an extensive perspective on global research landscape and evolving hotspots in the field of esophageal cancer immunotherapy. China leads in publication volume, with high-output institutions and authors concentrated in the country. This dominance is likely linked to the epidemiological characteristics of esophageal cancer in China, where over 50% of global cases and deaths occur.²³ Similar publication trends have been reported in a previous bibliometric analysis on PD-1/PD-L1 immunotherapy for esophageal cancer, which also noted China’s leadership in output but relatively lower citation impact.²⁴ However, countries like the Netherlands and Japan stand out in terms of citation impact, highlighting differences in research quality and thematic focus across nations. These findings that align with Bornmann & Leydesdorff’s observations on differential citation performance between high-output and high-impact countries.²⁵ Keyword co-occurrence analysis reveals a shift in research focus, from early studies on PD-1/PD-L1 inhibitors to growing attention on “biomarkers” and “tumor microenvironment,” indicating emerging priorities for future research. A thematic transition also documented in recent clinical reviews emphasizing the importance of predictive biomarkers and microenvironment-targeted strategies in EC immunotherapy.²⁶ Co-citation analysis underscores the pivotal role of clinical trial papers on drugs like Nivolumab and Pembrolizumab, which have become central references for optimizing treatment strategies. Additionally, co-citation clustering highlights the increasing importance of interdisciplinary research in areas such as “pharmacology” and “surgery,” which are laying the groundwork for new, multidisciplinary approaches to treating esophageal cancer.

Based on our bibliometric analysis, the trends of publications across different immunotherapy strategies in esophageal cancer over the past decade can be summarized. For immune checkpoint inhibitors, the number of publications has steadily increased since 2015, with China and Japan leading in output, reflecting both high disease burden and research capacity in these countries. Vaccine-related research, particularly dendritic cell-based strategies, shows a similar temporal growth pattern, with publications emerging earlier in Japan and later expanding in China, indicating a developing focus on this biologic approach. Publications on combination therapies, involving immune checkpoint inhibitors with chemotherapy, radiotherapy, or targeted agents, have also shown a marked increase in recent years, predominantly contributed by China, the United States, and Japan. Collectively, these trends highlight that research attention is increasingly diversified across multiple immunotherapeutic approaches, and the temporal and geographical patterns provide insight into the evolving focus and collaboration landscape in esophageal cancer immunotherapy research.

In bibliometric analysis, keyword bursts reveal emerging research hotspots within a specific time frame.²⁷ Early burst keywords in esophageal cancer immunotherapy include terms such as “pembrolizumab,” “checkpoint inhibitors,” “PD-L1,” and “dendritic cells.” Similar early-phase burst terms have been reported in previous immunotherapy-related bibliometric analyses, reflecting the foundational role of these molecules in shaping the research landscape.²⁸ PD-1 and PD-L1 inhibitors are now among most effective and broadly used cancer immunotherapies.²⁹ Pembrolizumab are monoclonal antibodies designed to inhibit the binding of PD-1 to its ligand, PD-L1, thus inhibiting the signaling pathway. This blockage activates lymphocytes, counteracts T-cell suppression, and strengthens body’s immune response against tumors.³⁰ Key trials like KEYNOTE-180, KEYNOTE-181, and ATTRACTION-3 underline the clinical efficacy of these inhibitors. Both pembrolizumab and nivolumab have demonstrated notable potential in managing advanced esophageal squamous cell carcinoma (ESCC). The KEYNOTE-180 and 181 trials demonstrated that pembrolizumab monotherapy substantially prolonged overall survival in advanced ESCC patients (9.3 vs. 6.7 months), particularly in those achieving combined positive score values of 10 or higher. Additionally, pembrolizumab exhibited a fewer incidence of grade 3 or higher immune-related adverse events (IRAEs) relative to chemotherapy.^22,31 Similarly, the ATTRACTION-3 study highlighted the benefits of nivolumab in subsequent therapy lines, showing significant improvements in overall survival (10.9 vs. 8.4 months) and a better safety profile.²¹ As a result, both nivolumab and pembrolizumab received approval as first-line options for ESCC cases with CPS ≥ 10 and as a broad second-line monotherapy.

Beyond immune checkpoint inhibitors, active vaccine therapies have also become an early research hotspot. This observation is supported by a bibliometric study on cancer vaccines, which identified “dendritic cells” among key early burst terms and highlighted its central role in vaccine development and tumor microenvironment interaction.³² Dendritic cell (DC) vaccine therapy is an innovative cancer immunotherapy strategy aimed at triggering cancer-specific immune responses through the presentation of tumor-associated peptide antigens.^33,34 Dendritic cells, which are highly effective at presenting antigens, capture dying tumor cells and process the associated peptides through major histocompatibility complex (MHC) molecules.³⁵ This process regulates T-cell responses by attracting both naive and memory T-cells, making DCs key players in cancer vaccine treatment.³⁶ In practice, monocytes are cultured to form immature dendritic cells, which are then matured with specific cytokines to enhance their T-cell activation function. The activated dendritic cells are subsequently administered to patients, where they prompt T-cells to migrate to antigen-expressing sites, triggering cytotoxic T-cell responses.^37,38 Preclinical studies have demonstrated significant anti-tumor effects of DC-based strategies on esophageal cancer cell lines,³⁹ with Phase II clinical trials assessing their feasibility and efficacy.⁴⁰ Given China’s dominant position in esophageal cancer immunotherapy research and the high prevalence of ESCC, which constitutes 90% of esophageal cancer patients in the country,⁴¹ the burst keyword “esophageal squamous cell carcinoma” reflects the focal point of research interest among Chinese scholars.

Despite the significant improvements in durable remission rates and manageable safety profiles observed with immunotherapy, monotherapy remains ineffective for over 67% of patients. Recent reviews and meta-analyses also support this trend, underscoring the clinical value of combining immune checkpoint inhibitors with chemotherapy, radiotherapy, targeted therapy, or anti-angiogenic agents to overcome resistance and improve outcomes.^42,43 As a result, researchers are increasingly focused on identifying new strategies to overcome resistance, particularly through combination therapies. The mechanism of action of immunotherapy combined with chemotherapy and radiotherapy involves multiple complex pathways. Chemoradiation not only directly kills tumor cells, releasing tumor antigens that enhance T-cell recognition,⁴⁴ but also upregulates the presentation of cell surface markers⁴⁵ and MHC-I molecules, thus strengthening immune recognition.⁴⁶ Additionally, chemoradiation remodels the tumor microenvironment, boosting lymphocyte infiltration,⁴⁷ activating dendritic cells, inhibiting regulatory T-cells, and promoting lymphocyte proliferation and migration, all of which enhance the overall anti-tumor immune immunity. In Checkmate-648, which evaluated the efficacy of dual immunotherapy, dual immunotherapy combining nivolumab and ipilimumab significantly improved overall survival in esophageal cancer patients, while demonstrating fewer severe treatment-related adverse events.⁴⁸ Furthermore, human epidermal growth factor receptor 2 (HER-2), an oncogene, exhibits overexpression in esophageal cancer, correlating with unfavorable prognosis prognosis.⁴⁹ Anti-HER2 agents reportedly upregulate PD-L1 expression on tumor cells,⁴² enhancing immunotherapy efficacy. Clinical studies reveal that pairing pembrolizumab and Margetuximab (a HER2-targeted monoclonal antibody) has demonstrated synergistic anti-tumor activity.⁵⁰ Moreover, data suggest that anti-angiogenic drugs can upregulate PD-L1 levels, reduce immunosuppressive cells such as regulatory T-cells, and enhance interactions between antigen-presenting cells and DCs. This boosts CD8+ T-cell infiltration, which in turn amplifies the anti-tumor immune response.⁵¹ Studies have also shown that in refractory esophageal squamous cell carcinoma, combining the anti-angiogenic drug apatinib with immune checkpoint inhibitors holds promising potential for improving patient outcomes.⁵²

The Tumor Microenvironment (TME) consists of cellular and non-cellular components surrounding tumor cells, comprising immune cells, extracellular matrix, blood vessels, and soluble molecules. It is essential in tumor initiation, progression, metastasis, and response to therapy.⁵³ It influences tumor formation, growth, invasion, and the effectiveness of treatments. Within this microenvironment, different components interact in complex ways – sometimes promoting tumor progression, while at other times potentially inhibiting it.⁵⁴ Among the key immunosuppressive actors in the TME are tumor-associated macrophages, especially the M2 subtype. Induced by IL-4, IL-13, IL-10, and M-CSF, M2 macrophages differ from cytotoxic M1 macrophages by promoting an anti-inflammatory environment that limits effective immune responses.⁵⁵ They also recruit regulatory T-cells through the secretion of CCL22, further enhancing immune suppression.⁵⁶ The immunosuppressive nature of the TME has been shown to limit the effectiveness of DCs-based vaccines.⁵⁷ One promising approach to remodel the TME and enhance immune activation is combining DC vaccination with radiotherapy.⁵⁸

Immunotherapy has demonstrated considerable promise in the treatment of esophageal cancer; however, further researches are critically needed to identify reliable biomarkers that predict therapeutic outcomes. The burst keyword analysis highlighted three potential biomarkers of interest: tumor mutational burden, tumor-infiltrating lymphocytes, and PD-L1 expression. Tumor mutational burden represents the mutation count present in tumor cells and is a key marker of genetic variability within a tumor.⁵⁹ Increasing evidence indicates that a high mutational burden correlates with better immunotherapy outcomes. This is because mutations can generate neoantigens, which, in turn, stimulate immune responses through T-cell activation.⁶⁰ Tumor-infiltrating lymphocytes, especially density of cytotoxic CD8+ T cells, provide insight into the immune cell infiltration in tumor microenvironment. Elevated TILs are frequently linked to better prognosis and enhanced responses to immunotherapy, suggesting that a strong immune presence within the tumor correlates with better therapeutic outcomes.⁶¹ PD-L1 expression on tumor cells serves as an immune-suppressive mechanism, dampening the immune response. While some studies indicate that PD-L1 expression may be linked to favorable outcomes with ICIs, its reliability and consistency as a predictive biomarker remain contentious.⁶² Finally, safety remains a critical concern in the widespread use of immunotherapy. New biomarkers are urgently needed to predict and mitigate severe immune-related adverse reactions, which could help expand the use of immunotherapies while minimizing harm to patients.⁶³

Despite the rapid growth of immunotherapy-related publications in esophageal cancer, several important knowledge gaps remain evident. First, although immune checkpoint inhibitors and combination strategies have become prominent research hotspots, mechanistic interpretations linking specific immune pathways, tumor microenvironment modulation, and therapeutic response are often insufficiently explored, with many studies focusing predominantly on clinical efficacy rather than underlying biological mechanisms. Second, while combination therapies are increasingly reported, the rationale for specific combinations and the determinants of synergistic versus antagonistic effects remain unclear, particularly in the context of heterogeneous tumor immune landscapes. Third, inconsistencies in study design, patient stratification, and outcome reporting across clinical and translational studies hinder direct comparison and synthesis of findings, limiting the generalizability of current evidence. In addition, the limited integration of bibliometric analyses with clinical trial data and functional validation studies constrains a comprehensive understanding of the translational trajectory from experimental immunotherapy approaches to clinical application. Collectively, these gaps highlight the need for more mechanism-oriented research, standardized clinical frameworks, and closer integration of epidemiological, translational, and functional evidence to advance immunotherapy in esophageal cancer.

This study provides a comprehensive bibliometric perspective on the clinical application of immunotherapy for esophageal cancer. Research outputs from China and other leading contributors offer important references for the global research community, underscoring the value of international collaboration in advancing more broadly applicable therapeutic strategies. The evolving landscape of research hotspots highlights the increasing focus on combination therapies, tumor microenvironment modulation, immune checkpoint inhibitors, and biomarker development, which together reflect the movement toward more precise and personalized immunotherapeutic approaches. Beyond summarizing existing research, this study leverages co-citation analysis and keyword burst detection to delineate emerging thematic structures within the field. Dendritic cell – based immunotherapy, tumor microenvironment remodeling, and immunotherapy-related biomarkers were identified as rapidly evolving yet comparatively underrepresented research frontiers. By mapping these themes systematically, this work offers a forward-looking bibliometric framework that complements existing narrative reviews and supports future clinical and translational research in esophageal cancer immunotherapy.

While providing a systematic analysis of the hotspots and trends in immunotherapy for esophageal cancer, this study has certain limitations. First, the data were exclusively drawn from the WOS Core Collection and are restricted to English-language publications, potentially overlooking valuable non-English studies. Nevertheless, the Web of Science Core Collection is widely adopted in bibliometric research due to its standardized citation indexing, stable data structure, and strong compatibility with co-citation and keyword-based analytical methods, which facilitate consistent and reproducible bibliometric analyses. Second, while keyword and co-citation analyses were employed, some aspects of the analytical process remain subjective, particularly in the removal of irrelevant high-frequency terms and the definition of thematic clusters, which may influence the presentation of results. Moreover, the limited time span of the study may not fully capture the most recent research developments. In addition, this study focused primarily on publication-based bibliometric indicators and did not integrate clinical trial registries, such as ClinicalTrials.gov, which may limit direct assessment of the translational trajectory of immunotherapy research in esophageal cancer. Although incorporating multiple databases or trial registries may increase coverage, it may also introduce heterogeneity in indexing standards and citation structures, potentially affecting analytical consistency. Future studies could address these limitations by incorporating multilingual databases and extending the observation period to improve comprehensiveness. Additionally, the application of more diverse bibliometric tools, combined with stronger interdisciplinary and international collaborations, may offer a more robust and holistic understanding of the evolving landscape of esophageal cancer immunotherapy.

Conclusion

This study applied bibliometric analysis to map the global research landscape of immunotherapy in esophageal cancer. Through co-citation and keyword analyses, the study identified key contributors, influential journals, and emerging thematic trends. Notably, a research focus shift was observed – from immune checkpoint inhibitors to combination therapies, tumor microenvironment modulation, and biomarker development-highlighting the field’s evolution toward personalized treatment strategies. By outlining these trends and their implications, this study offers a structured thematic framework that can inform future academic inquiry and clinical innovation in esophageal cancer immunotherapy.

Biography

Qiwei Zang is a distinguished Chief Physician and the Director of the Department of Thoracic and Cardiovascular Surgery at the Jiangsu Provincial People’s Hospital in Suqian. He is a graduate of Jiangsu University Medical School and a leading figure in the city’s key medical disciplines and clinical specialties. Dr. Zang currently serves as the Director of the Suqian Medical Association’s Thoracic and Cardiovascular Surgery Committee, a member of the Jiangsu Medical Association’s Thoracic Surgery Branch, and a member of the Jiangsu Research Hospital Association’s Lung Nodule and Lung Cancer MDT Committee. He specializes in the diagnosis and treatment of esophageal, lung, heart, and mediastinal diseases, with particular expertise in open and minimally invasive surgeries for esophageal cancer and lung cancer. In recent years, he has focused on minimally invasive surgeries for esophageal cancer and pulmonary nodules using thoracoscopic and laparoscopic techniques. Dr. Zang has led two municipal-level research projects, authored one monograph, co-authored another, and published over ten papers at the provincial level or above. He has also received three Suqian Science and Technology Progress Awards.

Funding Statement

This work was supported by Key R&D Plan for Science and Technology Projects in Suqian City [Z2019130].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets presented in this study can be found in online repositories Figshare with the identifier https://doi.org/10.6084/m9.figshare.27877032.

Ethical approval statement

This study did not involve human participants or animals, and therefore ethical approval was not required.