A bibliometric analysis of immune response in oral cancer

Abstract

Background

Oral squamous cell carcinoma (OSCC), a type of oral cancer, has a high mortality rate and unfavorable outcomes. Its tumor microenvironment (TME) is intricate and adaptable, with research frequently focusing on the immune reaction. Scholars are exploring ways to enhance survival by bolstering the immune response within the TME. However, a comprehensive trend analysis is lacking. Bibliometric analysis can address this by visualizing research patterns. This study aimed to map these trends in OSCC immunology from 2003 to 2023.

Methods

An immunology-focused search on OSCC was executed within the Web of Science Core Collection, spanning 2003 to 2023. Despite its narrow focus, the search offers a telling glimpse of current researches in this domain. Bibliometric analysis was performed using VOSviewer, Citespace, Scimago Graphica, and R software.

Results

From 2003 to 2023, the field has published 805 publications, predominantly from China and the United States. The most valuable contributing author is Friedman Jay, topping co-citation counts. The journal Oral Oncology is the leading journal with the highest publication volume. An analysis of keyword bursts indicated that research into nivolumab and chemotherapy is a prevalent area of interest within the clinical community. These findings suggest that neoadjuvant immunotherapy represents a promising avenue for future therapeutic development.

Conclusions

This study presented a summary of the current trends and research frontiers in the field of immunological aspects of OSCC. This summary can serve as a valuable reference and a source of new insights into this area of research.

Background

As summarized by Hyuna Sung in 2020, the incidence and mortality rates of oral cancer (OC) are frequently high in South Central Asia, particularly in the case of oral squamous cell carcinoma (OSCC) [1]. Several factors may contribute to the development of OSCC, including prolonged alcohol consumption, inadequate oral hygiene, excessive sun exposure, betel nut consumption, prolonged foreign body stimulation, malnutrition, mucosal leukoplakia or erythema, and oral ulcers [2]. With greater frequency in certain locations, such as the blade of the tongue and the floor of the mouth, in the case of OSCC. Other frequently affected areas include the palatines, buccal mucosa, lips, and gingiva [3]. OSCC exhibits variations in clinical development and progression depending on the site of occurrence. Tongue squamous cell carcinoma is among the most common types of OSCC, accounting for approximately 25%–50% of cases. Due to the mobility of the tongue,this cancer type is associated with a higher likelihood of occult presentation and cervical lymph node metastasis compared to other sites [4, 5]. In recent years, there has been a lack of significant improvement in the overall 5-year survival rate for OSCC. The 5-year survival rate for early-stage oral cancer is 80%, whereas the rate for advanced lesions is just 20% [6].

Numerous therapeutic approaches have been implemented and refined to enhance survival rates. Surgical intervention remains the primary treatment modality for OSCC, aiming to remove the primary lesion while preserving function and aesthetics. However, accurately defining the margins of excision for a given lesion remains a challenge [7]. Excessive excision may negatively impact the quality of life of the patient post-operatively [8]. This approach is often complemented by radiotherapy or chemotherapy, though radiotherapy has significant limitations and can cause damage to surrounding normal tissue [9]. Chemotherapy, while effective in some cases, is associated with numerous adverse effects, including physical discomfort and profound psychological impacts [10]. Advancements in research suggest that neoadjuvant immunotherapy holds promise as a more effective treatment option [2, 11]. Immunotherapy has been proposed for cases where radical surgery or radiotherapy is not feasible [12]. While neoadjuvant immunotherapy for OSCC has yet to receive formal approval from the European Union, large-scale clinical trials have demonstrated promising outcomes [13]. Studies have highlighted the roles of immune checkpoints (e.g., CTLA-4, PD-1, and LAG3) in tumor treatment. The synergistic potential of combining different immune checkpoint blockade therapies has opened avenues for developing neoadjuvant immunotherapy approaches [14].

Cancer, caused by mutations in cancer cells, is also linked to immune system imbalance. Past research emphasized cancer cells over immune cells, with a common strategy of directly targeting cancer cells, which might miss addressing the root cause or preventing recurrence. Emerging views suggest that enhancing the immune response within the tumor microenvironment (TME)—which includes various immune cells, stromal cells, and the extracellular matrix—could be a more effective strategy, given the TME’s dynamic and complex nature [15, 16].

Many new targeted TME therapies are available but show limited effectiveness, likely due to the TME’s complexity and changeability. T cells, the key component, can act as both tumor killer and facilitators of immune evasion [17]. Their transformation to a state of exhaustion, due to chronic antigen exposure, impairs their ability to fight tumors [18]. Research by Wherry and Kurachi indicates this exhaustion can be a protective mechanism gone awry, leading to immunosuppression and tumor growth [19]. Although the link between immune checkpoints and oral cancer is not fully understood, and some patients do not respond well to immune checkpoint blockade (ICB) therapy, it is essential to discover new targets and clarify their mechanisms within the TME for more precise treatment.

Literature summaries exploring the immune link to OSCC often lack organization, failed to provide a coherent understanding of the potential role and benefits of immunotherapy in OSCC. As mentioned above, neoadjuvant immunotherapy is not yet the preferred option despite its evaluation in numerous clinical trials. Several factors may contribute to this: the mechanisms by which immunotherapy affects oral cancer are poorly understood, the topic may not be a major focus of research, or immunotherapy might not yet demonstrate comparable effectiveness to conventional therapy. Therefore, synthesis articles and robust data on research hotspots and trends in this area are limited. Bibliometric analysis, a powerful method for analysis and induction, can aid in swiftly comprehending the development network and frontier hotspots in the academic field through graphical visualization [20]. Tools such as CiteSpace, VOSviewer, and other relevant factors are utilized to organize extensive datasets into interconnected categories, including institutional affiliations, authorship, introductions, geographical origins, journals, and other relevant factors. This method allows for an objective evaluation of individual and collective contributions and the anticipation of emerging research trends within this field [21–23]. This study employs a bibliometric analysis of research on OSCC and progression of immunotherapy from 2003 to 2023. This approach facilitates the mapping of study distribution, identification of study hotspots, prediction of future trends, and contribution to the development of the research platform.

Methods

Data collection

PubMed is a typical abstract-type database, containing mainly literature abstracts, whereas the Web of Science (WOS) Core Collection is a citation-type database, containing citation information in addition to literature abstracts. Both Scopus and WOS cover mainly the natural sciences, engineering, and biomedical research, but Scopus outperforms WOS in terms of coverage of the social sciences and humanities. However, WOS is the most widely used citation database for scientometric analysis [24, 25]. WOS may not include all relevant publications, leading to potential omissions in bibliometric studies [26]. However, it does contain a large body of scientific literature across a range of subject areas, making it highly suitable for identifying a corpus of reviews or articles that meet specific criteria [27]. The restrictions are as follows: Topic = (“oral cancer” OR “oral squamous cells carcinoma” OR “tmcc” OR “tongue cancer” OR “tongue squamous cells carcinoma”) and (“immune” OR “immune checkpoint” OR “T cell” OR “T-cells” OR “T cells” OR “T cells exhaustion” OR “exhausted T cells” OR “T-lymphocyte” OR “T Lymphocytes” OR “immune escape” OR “PD-1/PD-L1”). The search spanned from 2003 to 2023. A total of 807 results were obtained, comprising two document types: articles and reviews. After screening, 805 English-language articles were exported. The process of screening the resulting table and exporting the data is illustrated in the figure below (Fig. 1 and Table 1).

Fig. 1.

Process of obtaining data

Table 1.

Screening criteria for the study

Category	Specific standard requirements
Research database	Web of Science core collection
Citation index	All
Searching period	2003–2023
Language	“English”
Searching topic	(“oral cancer” OR “oral squamous cells carcinoma” OR “tmcc” OR “tongue cancer” OR “tongue squamous cells carcinoma”) AND (“immune” OR “immune checkpoint” OR “T cell” OR “T-cells” OR “T cells” OR “T cells exhaustion” OR “exhausted T cells” OR “T-lymphocyte” OR “T Lymphocytes” OR “immune escape” OR “PD-1/PD-L1”)
Document types	“Article” OR “Review Article”
Subject categories	All
Data extraction	Export with full records and cited references in plain text format
Search results	805

Data analysis and visualization

A variety of tools were employed for data analysis and visualization of the results, including VOSviewer(1.6.20.0), CiteSpace(6.3.1.0), Scimago Graphica(1.0.42.0) and Microsoft Excel 2021. VOSviewer is a Java-based bibliometric analysis software that can be employed to explore and visualise the characteristics of a scientific field from a variety of perspectives, including publications, countries, authors, journals, references, and so forth [28]. This is achieved by importing paper data, which enables the generation of three main types of graphs: network visualization graphs, overlay graphs, and density visualization graphs. The network visualization graph is the most extensively analyzed, where all the data are clustered according to an algorithm, with different colors used to differentiate between them. Each cluster comprises distinct nodes that correspond to a specific parameter, such as country/region, institution, journal, author, or keyword. Node size reflects the strength or citation count of the parameters, while the thickness of connecting lines represents the strength of associations between different parameters. CiteSpace, another Java-based visualization tool, provides options for visualizing outbreak citations and web maps [29]. Its keyword outbreak map, in particular, highlights temporal and quantitative distributions of keyword trends facilitating rapid identification of sudden increases in scientific activity and facilitating trend analysis. Scimago Graphica was used to visualize publication counts and international collaborations across countries [30]. Each tool played a specific role collectively contributing to this study.

Results

The trend of publications worldwide

A total of 805 documents on immunological studies of OC were downloaded from the WOS database between 2003 and 2023, comprising 622 articles and 183 reviews. A time-series graph was created to illustrate the number of publications over time (Fig. 2). The data shows that from 2003 to 2009, the number of documents remained below 20. Between 2010 and 2015, the number fluctuated annually between the upper and lower 20. After 2015, the number of publications increased to over 40, with a notable surge in 2021, where studies grew by over 100. The fitted regression line formula for this trend, R² = 0.9459, indicated a well-fitted regression. The number exhibits a cyclical fluctuation every 5–6 years, with an overall upward trend. A superficial analysis of the data revealed that the number of publications in this field fluctuates suboptimally every 5–6 years and grows steadily within a certain range. Of these 805 articles, 41.74% were published in the last 3 years.

Fig. 2.

Worldwide publication trends in research on the immune system in OC

The contributions of the countries and institutions

The 805 documents originated from 56 countries and 1228 institutions. The top ten countries with six or more documents were mainly in Asia and Europe, followed by South and North America. China led with 258 publications, followed by the United States (n = 201), India (n = 90), Japan (n = 73), and Germany (n = 44). The quality of the United States publications is superior due to the fact that it has published the greater number of articles and has been cited per article the most frequently (average citation = 34.54). While China and India ranked in the top three, with 4,052 and 1,232 citations, respectively, their average citations per article were much lower than European countries in the latter position. European countries, such as Germany (average citation = 28.66), the United Kingdom (average citation = 25.83), and Sweden (average citation = 22.48), exhibit a higher average number of citations per article (Fig. 3a). This suggests that the quality of articles published in Asia may need improvement and European countries produce more sophisticated and influential studies in this field, offering scholars a wealth of knowledge to leverage. The underlying causes of this phenomenon may be associated with constraints in state funding and the absence of universal screening for oral cancer [31]. To better understand the intersections between these countries, a linking circle diagram is presented in Fig. 3b. The visual map shows China at the center, significantly overlapping with the United States of America, indicating substantial contributions from these two countries. Meanwhile, the United States of America has the most extensive collaborative efforts, particularly with China, India, Germany, and Brazil. The country time charts also highlight China, Cyprus, Armenia, and Indonesia as particularly innovative in this field (Fig. 3c). China Medical University has been the focus of the greatest number of research studies in this field, while Sichuan University has been the most frequently cited institution (Fig. 3d).

Fig. 3.

Analysis of countries and institutions in the field of OC immunity worldwide. Panel (a) displays the graph of publications and citations. The board color represents a higher average citation rate. Panel (b) shows the interaction strength among all 56 countries using SCImago Graphica. The degree of international collaboration is depicted by the size of the circles (number of publications) and the connecting lines (cooperation). The overlap map (c) represents the timeline of every country using VOSviewer. The size of the nodes represents the number of publications, the lines between the nodes represent collaborations, and the color shades represent the years in which the country published the relevant research. The trend chart (d) depicts the top ten institutions conducting research on OC immunity worldwide. The size of the circles represents IF

Analysis of the authors and the co-cited authors

A total of 4,866 authors contributed to the 805 immunity studies on oral cancer, with 15 core authors publishing ≥ 6 documents (Fig. 4a). The most prolific authors were Salo Tuula and Ries Jutta, each with 10 articles. The most cited author is Allen Clint T, with 9 publications and 378 times, averaging 42 citations per article. The author with the highest average citations per article was Friedman Jay, with 58.5 citations from only six articles, indicating significant impact and influence in the field (Fig. 4a). Using VOSviewer, we visualized the relationships between authors with ≥ 6 publications, revealing 507 nodes, 22 clusters, and 3,221 links. Allen Clint T. is at the center of the network, collaborating most closely with Moore Ellen C. (Fig. 4b). However, their research primarily focuses on 2017 and is not considered novel (Fig. 4c). There are 29,498 co-cited authors in the field, filtered to show those with a minimum of 40 publications. The most co-cited authors are Robert L. Ferris (n = 120), followed by Ahmedin Jemal (n = 106) and Saman Warnakulasuriya (n = 99) (Fig. 4d).

Fig. 4.

Analysis of authors and co-authors in the field of OC immunity worldwide. The plate chart (a) includes the number of documents and citations of authors. The network map (b) and overlay map (c) show the interaction of authors. The size of the nodes represents the number of publications, the lines between the nodes represent the mutual collaboration, and the color shades represent the publication time of the authors' related research. The density map (d) shows the interaction of co-cited authors. Darker colors indicate more citations, and the size and distribution of the circles indicate the degree of collaboration between authors

Analysis of journals and co-cited journals

A total of 338 journals published OC-related immunity studies. The top three journals were Oral Oncology (n = 54), Cancers (n = 35), and Oral Diseases (n = 19). The journal with the highest impact factor was Frontiers in Immunology (IF = 7.3), followed by the International Journal of Molecular Sciences (IF = 5.6) (Fig. 5a). Correlation visualizations for 64 journals with ≥ 3 publications revealed that Oral Oncology, the journal with the highest publication volume, has a strong citation relationship with Cancers and the International Journal of Molecular Sciences (Fig. 5b). The time-series graph indicates that the most recent studies are published in Cell and Biomedicine (Fig. 5b). As shown in Fig. 5c, among the 4,636 co-cited journals, two were cited more than 1000 times: Oral Oncology (1,659 times) and Cancer Research (1277 times). The impact factors of the top 10 co-cited journals vary significantly, with Nature (IF = 64.8) and Cell (IF = 64.5) (Fig. 5c). A co-citation network graph based on 29 journals with minimum citation count of 300 reveals three clusters, each represented by a different color. The red cluster comprises high-impact journals such as Nature, Cell, Science, and Cancer Research, representing the forefront and highest level of each field. The blue cluster is centered around Oral oncology, while the green cluster focuses on immune-based studies. Oral oncology has a positive co-citation relationship with the Journal of Oral Pathology & Medicine, the International Journal of Cancer, Clinical Cancer Research, and Cancer Research (Fig. 5d).

Fig. 5.

Analysis of journals and co-cited journals in the field of OC immunity. The trend chart (a) shows the top ten journals. The overlay map (b) shows the interaction of journals timely. The trend chart (c) shows the top ten co-cited journals. The network map (d) shows the interaction of co-cited journals. The size of the circles in graphs a and c represent the number of citations. The size of the nodes in graphs b and d represent the number of publications, the lines between the nodes represent the collaborations, and the colors represent the categories

Analysis of commonly cited references

Over the last 20 years, there have been 40,120 co-cited references on oral cancer immunology studies. The most frequently cited article is “Global Cancer Statistics” by Ahmedin Jemal, with 85 citations. Published in CA:A Cancer Journal for Clinicians, with an impact factor of 254.7, it leads the list [32]. Additionally, two other references comprising ≥ 50 citations include “Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck” (n = 65) by R.L.Ferris and “Hallmarks of Cancer: The Next Generation”(n = 57) by Douglas Hanahan, published in the New England Journal of Medicine and Cell, respectively [33, 34]. Furthermore,the graph shows that most of the highly cited studies were published between 2011 and 2016 (Fig. 6a). References with ≥ 20 citations were visualized for correlation using VOSviewer. The visualization shows that “Global cancer statistics” by Jemal exhibited a positive co-citation relationship with “Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck” and “Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study” by Barbara and Cohen (Fig. 6b) [35].

Fig. 6.

The trend chart (a) shows the top ten co-cited references in the field of OC immunity. Circle size for citation count, color for category, color depth for IF size, position for publication year. The network map (b) shows the interaction of co-cited references. The size of the nodes represent the number of publications, the lines between the nodes represent the collaborations, and the colors represent the categories

Keyword analysis

Keywords encapsulate the essence of a paper, and keyword co-occurrence can highlight research hotspots [36]. In this study, VOSviewer was employed to analyze 805 documents and produce a network view of keyword co-occurrence. A total of 4,005 keywords were identified, with 31 keywords (≥ 30 occurrences) selected for visualization (Fig. 7a). High-frequency keywords such as “oral cancer,” “immunotherapy,” “survival,” and “T-cells” represent core research themes. The map displays three clusters—red, green, and blue—each representing distinct research directions. The red cluster focuses on “oral cancer,” including keywords such as growth, progression, apoptosis, inflammation, mechanism, and treatment, addressing the process of oral cancer development and its mechanisms. The green cluster focuses on “squamous cell carcinoma,” incorporating keywords such as “HPV,” “prognosis,” “recurrence,” “risk,” “survival,” “tumor-infiltrating lymphocytes,” and “T-cells,” highlighting research on T-cell function to address the low survival rate, high recurrence rate, and poor prognosis of squamous cell carcinoma. Meanwhile, the blue cluster focuses on “immunotherapy,” including keywords such as “dendritic cells,” “immunotherapy,” “regulatory T-cells,” and “tumor microenvironment,” investigating the mechanisms and efficacy of immunotherapy. This area has become a major research focus in recent years, with efforts aimed at improving both TME and immune environment. A keyword outbreak indicates a surge in citations for a term during a specific period, highlighting it as a research hotspot. A decrease in node frequency suggests that the term is fading, while minimal change indicates enduring relevance. The analysis reveals that from 2005 to 2018, key terms such as apoptosis, gene expression, invasion, progression, immune response, and neck cancer, focused on tumor progression and gene targets. After 2019, research shifted toward the TME, chemotherapy, and immunotherapies like nivolumab, targeting OC recurrence. These are likely the current research hotspots in OC immunology (Fig. 7b).

Fig. 7.

The network map (a) and outbreak graph (b) of keywords in the field of OC immunity. The nodes in Fig. 7a represent keywords, their size represents importance, and the colors represent different categories. The red color in Fig. 7b represents the frequency of occurrence of the words, the darker the color, the higher the frequency of occurrence, and the length of the nodes represents the importance and time persistence

Discussion

This study retrieved 805 publications on immunity research in oral cancer from the WOS covering the period from 2003 to 2023.

In terms of temporal trends, the number of studies in the field has surged since 2016. This growth is attributed to the expansion of approved indications for the use of PD-(L)1 inhibitors (e.g., nivolumab), which was approved by the Food and Drug Administration (FDA) in 2014 [37]. Head and neck squamous cell carcinomas (HNSCC), including oral cancers, have been widely studied since 2015, particularly focusing on recurrent or metastatic HNSCC after previous treatments [38]. The approval of nivolumab for marketing in China marked the advent of a new era for immunotherapy in HNSCC [39]. Oncological immunotherapy is increasingly being integrated with surgery, chemotherapy, radiotherapy, and targeted therapies to provide patients with novel treatment options [40]. In the last 5 years, resistance and non-response to PD-1/PD-L1 blockade therapy have spurred interest in new immune checkpoints (e.g., CTLA-4, TIM-3, and LAG-3) and other targets to salvage T-cell function and inhibit tumor immune escape through combination therapy [41]. A study by Aeryon Kim et al. demonstrated that blocking LILRB1 enhances CD8⁺ T cell-mediated tumor killing in tumors induced by dual anti-hot target protein (BiTE). This finding suggests that blocking LILRB1 could be a viable therapeutic strategy to boost T cell-targeting therapies [42]. In conclusion, immunotherapy for OSCC remains in its early stages.

Over the past two decades, an analysis of the number of publications reveals that China has made the highest academic contribution in this field, with six of the top ten institutions originating from China. Other countries in the top 10 institutions are North America, South America, Asia, and Europe, with an equal distribution between Asia and Europe. This distribution might be attributed to the high incidence of oral cancer in South Asian countries like India, Sri Lanka, and China, where smoking and betel quid chewing are prevalent. These irritants increase the risk of oral cancer development [43, 44]. The United States was the second-largest contributor, with two of the top ten institutions. European countries, such as Germany and the United Kingdom, also demonstrated significant contributions. Enhanced international collaboration between countries and institutions could further reduce the incidence and recurrence of OSCC.

Among the top 10 journals, Oral Oncology published over 50 papers, followed by Cancer with over 30, while the remaining journals published fewer than 20. Commonly cited journals are Oral Oncology, Cancer Research, Clinical Cancer Research and the Journal of Oral Pathology & Medicine. These specialized journals, focusing on head and neck disorders, appear in both the top ten publishing and co-cited journals, reflecting their prominence in this research area. Research on immunity in OSCC is predominantly published in molecular biology, immunology, pharmacy, oncology, and clinical journals. This distribution underscores the widespread attention the field has garnered and reflects its substantial progress in both basic research and clinical applications.

From the authors’ perspective, both Salo Tuula and Ries Jutta have authored 10 relevant articles. However, Salo Tuula’s work has garnered more citations, indicating a higher perceived impact. Meanwhile, Friedman Jay, Van Waes Carter, Uppaluri Ravindra, and Allen Clint T. have higher average citations per article, indicating the superior quality of their contributions. Allen Clint T. has collaborated extensively with other researchers. His work demonstrated that PD-1 expression on of T-cell surfaces plays a role in the functional immuno-explicit mechanisms of independent T-cell clones within progressive tumors. Additionally, he supported neoadjuvant PD-1 checkpoint blockade therapy in surgically resected patients alongside Moore and Friedman in 2019 [45]. In 2023, Allen et al. demonstrated that neoadjuvant therapy induced HPV-specific tumor T-cell responses in patients with newly diagnosed HPV-associated oropharyngeal squamous cell carcinoma, with this approach also linked to prognosis [46]. In 2024, they published a study on the suppression of T-cell function by tumor-infiltrating neutrophils. Using a homozygous murine OC model in immunocompetent mice, they measured plasma cytokine concentrations and associated immune functions via proteomics and functional immunoassays. Their findings revealed that complete primary tumor resection mitigated neutrophil-driven systemic immune suppression and potentially enhanced the efficacy of neoadjuvant immunotherapy [47]. Allen’s research focuses on the immunological mechanisms of head and neck cancer development, progression, and treatment, establishing him as a pioneer in the field. Another notable contributor is Robert L. Ferris, the most co-cited author in this study. As a physician-scientist, Ferris is dedicated to advancing the development and implementation of immunotherapies, which stimulate the immune system of the body to target and inhibit cancers. He leads a distinguished team of scientists collaborating internationally to translate basic scientific discoveries into clinical immunotherapy, advancing treatment for head and neck cancer as well as other malignancies [20, 48, 49].

In this study, the top ten co-cited references, each cited at least 20 times, were identified. These included two reviews and eight articles published between 2008 and 2019, categorized into three main groups: global cancer epidemiology statistics [32, 50–52], oral cancer genomics analysis [34, 53], and clinical trial papers on nivolumab, pembrolizumab, and cetuximab [33, 54, 55]. Nivolumab and pembrolizumab, the first FDA-approved monoclonal antibodies targeting PD-1 for neoadjuvant immunotherapy of HNSCC, have achieved remarkable clinical success, solidifying their role as essential treatments [33]. Despite their individual efficacy, their therapeutic effects are often transient. Therefore, combination therapies, such as neoadjuvant immunotherapy using monoclonal antibodies, either in combination with each other or alongside chemotherapy or targeted therapies, have become a new approach. Tian et al. assessed three patients with OSCC who responded well to neoadjuvant immunotherapy combined with nimotuzumab (anti-EGFR) and paclitaxel. Their findings demonstrated notable tumor shrinkage, with some cases even experiencing complete tumor disappearance. Notably, despite variations in tumor mutational burden prior to treatment, all patients exhibited significant macrophage infiltration and PD-L1 expression. This suggests that macrophages with a high proportion of CD68 + PD-L1 + cells may serve as a promising biomarker for the success of combined neoadjuvant immunotherapy in HNSCC [56]. Haddad et al. compared the clinical benefits of nivolumab combined with ipilimumab with the EXTERME regimen (cetuximab plus cisplatin/carboplatin plus fluorouracil for six cycles, followed by cetuximab maintenance) in recurrent/metastatic HNSCC. While no statistically significant difference in overall survival was observed, combination therapy exhibited a favorable safety profile, improved quality of life, and extended time to symptomatic progression [57]. Kato et al. advocated the use of nivolumab combined with ipilimumab or chemotherapy as a novel first-line treatment for Japanese patients with advanced esophageal squamous cell carcinoma [58]. Additionally, a recent study by Hanna et al. explored a non-randomized clinical trial targeting precancerous lesions, demonstrating the potential clinical efficacy of nivolumab in high-risk proliferative verrucous leukoplakia (PVL). This provides preliminary evidence or future trials aimed at preventing the progression of PVL into OC [59].

Keywords are the core of an article, summarizing that nivolumab, chemotherapy, recurrence, and TME represent the primary directions of immunity research in OSCC. Keyword clustering analysis identified major categories such as squamous cell carcinoma, TME, immunotherapy, and inflammation. In basic research, current trends primarily focus on blocking the PD-1/PD-L1 axis and rejuvenating the immune function of exhausted T-cells to target and eliminate tumors. Clinically, immunotherapy aimed at improving the TME has emerged as a critical research hotspot in recent years. Nivolumab is used either as monotherapy or in combination with chemotherapy [15]. Tumor immunotherapy, leveraging on the complex microenvironment of OSCC, specifically targets cancer cells by activating the host’s immune system. This approach is effective not only for treating primary tumors but also for metastatic tumors [2]. In practice, however, immunotherapy targeting immune checkpoints (e.g., nivolumb) in OSCC has yielded preliminary outcomes in clinical settings. Some patients have demonstrated marked responses to immune checkpoint inhibitors [60], while others have not responded to this treatment or have experienced sustained efficacy for a period of time before experiencing treatment failure or relapse [33, 61]. Non-response and resistance represent a significant challenge in the clinical management of OSCC. These phenomena may be related to the diverse tumor biology and response patterns observed among patients, suggesting that nabumab be combined with individualized treatment strategies involving other modalities, such as chemotherapy, radiotherapy, or targeted therapies [62]. Another nascent CAR-T therapeutic, while demonstrating minimal advancement in the treatment of oral cancer, has yielded significant breakthroughs in the domain of hematological oncology and in select solid tumors [63]. For instance, a novel autologous CD19-specific CAR-T therapy, designated ssCART-19, exhibited a favorable safety profile in a phase I clinical trial involving patients with relapsed or refractory B-cell acute lymphoblastic leukemia. In the 17 patients, no instances of grade 4 cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or related deaths were observed. The overall response rate for ssCART-19 at 3 months was 87.5%, including 62.5% complete response [64]. Furthermore, the utilisation of automated technology to generate CAR-T cells that target CLDN6, in conjunction with the potential deployment of CLDN6-encoding mRNA vaccines, enhances the therapeutic efficacy of recurrent/refractory CLDN6-positive solid tumours. This approach facilitates the augmentation of the immune system's capacity to recognise and eliminate cancer cells [65]. Notably, therapeutic vaccines, particularly mRNA vaccines, have also made noteworthy advancements in both research and application. Lorenzo Azzi and colleagues conducted the inaugural investigation into a preclinical experimental model of therapeutic vaccination in a mouse OSCC MOC2 cell line stably expressing MHC class II antigens (MOC2-CIITA) following CIITA gene transfection. Mice that received injections of MOC2-CIITA exhibited rejection or significant retardation of tumor growth. Of particular note, vaccinated animals that completely rejected MOC2-CIITA tumors demonstrated anti-tumor immune memory, thereby resisting challenge by parental MOC2 tumor cells. This represents an unprecedented novel immunotherapy for oral cancer and opens new avenues for future human tumor treatment [66]. The advent of novel immunotherapies has led to a diversification of treatment options for oral cancer patients, with these therapies becoming increasingly prevalent in the context of oral cancer treatment.

This study has several limitations. First, the data were collected from a single database (WOS), potentially overlooking publications from other sources. Secondly, it should be noted that the analysis is limited to English-language papers, which may introduce a certain degree of bias in the source material. In order to ensure the objectivity and comprehensiveness of the data set, incomplete publications from 2024 were excluded. However, the lack of data may hinder our ability to identify trends, assess the impact of citations, and analyse patterns of collaboration. Therefore, after collecting data on all publications in 2024, we propose to update the dataset in the next phase. Finally, the quality assessment of the included studies was based solely on the authors’ attention, restricting the approach. Incorporating a standardized quality scoring tool in future studies could provide a more robust evaluation of relevant OSCC immunity research. During the analysis, we observed that the majority of the articles focused on clinical research concerning the efficacy of neoadjuvant immunotherapy, either alone or combined with other therapies. However, there is a paucity of in-depth exploration regarding the specific role of immunity in OSCC and its target mechanisms.

Furthermore, there is a notable absence of authoritative and innovative discoveries in this area. Most scholars have concentrated on inhibiting the development of the disease, reducing its recurrence, or mitigating drug resistance. However, there remains a knowledge gap concerning prevention strategies. Improving the prognosis of OSCC is crucial. However, addressing this issue primarily relies on early detection, diagnosis, and treatment. Hence, it is imperative to study the pathogenesis and immune response of OSCC from preventive and therapeutic perspectives to tackle clinical challenges. In summary, OSCC immunity research demonstrates a promising developmental trend in both basic research and clinical translation.

Conclusions

Advancements in science and technology, combined with a deeper understanding of immunotherapy, have brought neoadjuvant immunotherapy, represented by nivolumab, into the spotlight. Its significant benefits have been demonstrated both as monotherapy and in combination with other treatments. The bibliometric analysis in this study underscores the importance of OSCC as a major disease that warrants greater attention. Addressing the formidable challenges in cancer treatment requires prioritizing investigations into neoadjuvant immunotherapy. In the future, it is important to explore more effective combination therapies based on neoadjuvant immunotherapy. Additionally, a meta-analysis of immune checkpoint inhibitors in OSCC is necessary to compare the efficacy, safety, tolerability, and factors affecting the efficacy of this treatment. However, substantial progress is still needed to unlock their full therapeutic potential and advance of this promising field.

Abbreviations

OC

Oral cancer

OSCC

Oral squamous cell carcinoma

WOS

Web of science

FDA

Food and drug administration

HPV

Human papillomavirus

EGFR

Epidermal growth factor receptor

HNSCC

Head and neck squamous cell carcinoma

IF

Impact factor

TME

Tumor microenvironment

ssGSEA

Single-sample gene set enrichment analysis

CAF

Cancer-associated fibroblasts

CTSG

Cathepsin G

CAR-T

Chimeric antigen receptor T-cell

MHC

Major histocompatibility complex

Author contributions

Rongrong Zhang worte the main manuscipt text,Runying Guo prepared Formal analysis and Data curation, Yuqi Xin is responsible for Project administration and Investigation and Qingkun Jiang is responsible for fomal analysis. Jiaxuan Qiu is responsible for Methodology, Investigation and Funding acquisition.All authors reviewed the manuscript.

Funding

This research was supported by National Natural Science Foundation of China (No. 82260194, 82403716), Jiangxi Natural Science Foundation (No. 20232BAB216073, 20242BAB25514), and Key Projects of Jiangxi Administration of Traditional Chinese Medicine (No. GZY-KJS-2023–028).

Data availability

All data generated or analysed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Review and/or approval by an ethics committee as well as informed consent was not required for this study because this article only used existing data from published studies and did not involve any direct experimentation/studies on living beings.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.