Insights into the historical trajectory and research trends of immune checkpoint blockade in colorectal cancer: visualization and bibliometric analysis

Bibliographic data are from the Web of Science Core Collection (WoSCC). These include Science Citation Index Expanded, Social Sciences Citation Index, Arts & Humanities Citation Index, Emerging Sources Citation Index, Current Chemical Reactions and Index Chemicus (12). To avoid bias caused by the daily database updates, all the publications from 2000 to 2022 were retrieved and downloaded on November 16, 2023. The search strategy was as follow: (TS=(ipilimumab OR pembrolizumab OR nivolumab OR immunotherapy OR “immune checkpoint blockade” OR “immune checkpoint inhibitor” OR PD-1 OR PD-L1 OR CTLA-4) OR TI=(ipilimumab OR pembrolizumab OR nivolumab OR immunotherapy OR “immune checkpoint blockade” OR “immune checkpoint inhibitor” OR PD-1 OR PD-L1 OR CTLA-4 OR yervoy OR Keytruda OR opdivo) OR AB=(ipilimumab OR pembrolizumab OR nivolumab OR immunotherapy OR “immune checkpoint blockade” OR “immune checkpoint inhibitor” OR PD-1 OR PD-L1 OR CTLA-4 OR yervoy OR Keytruda OR opdivo)) AND (TS=(“Rectal Neoplasm” OR “Rectal Tumor” OR “Rectal Cancer” OR “Rectum Neoplasm” OR “Rectum Cancer” OR “Cancer of the Rectum” OR “Cancer of Rectum” OR “Colorectal Neoplasm” OR “Colorectal Tumor” OR “Colorectal Cancer” OR “Colorectal Carcinoma” OR “Colonic Neoplasm” OR “Colon Neoplasm” OR “ Cancer of Colon” OR “Colon Cancer” OR “Cancer of the Colon” OR “Colonic Cancer” OR “CRC”) OR TI=(“Rectal Neoplasm” OR “Rectal Tumor” OR “Rectal Cancer” OR “Rectum Neoplasm” OR “Rectum Cancer” OR “Cancer of the Rectum” OR “Cancer of Rectum” OR “Colorectal Neoplasm” OR “Colorectal Tumor” OR “Colorectal Cancer” OR “Colorectal Carcinoma” OR “Colonic Neoplasm” OR “Colon Neoplasm” OR “ Cancer of Colon” OR “Colon Cancer” OR “Cancer of the Colon” OR “Colonic Cancer” OR “CRC”) OR AB=(“Rectal Neoplasm” OR “Rectal Tumor” OR “Rectal Cancer” OR “Rectum Neoplasm” OR “Rectum Cancer” OR “Cancer of the Rectum” OR “Cancer of Rectum” OR “Colorectal Neoplasm” OR “Colorectal Tumor” OR “Colorectal Cancer” OR “Colorectal Carcinoma” OR “Colonic Neoplasm” OR “Colon Neoplasm” OR “ Cancer of Colon” OR “Colon Cancer” OR “Cancer of the Colon” OR “Colonic Cancer” OR “CRC”)). The detailed search strategy is shown in Supplementary Material 1 (13–15). Finally, only the research papers and review articles in English were considered for this study.

A total of 7,595 documents were retrieved from WoSCC, and after excluding non-research papers and review articles there were 6,786 that met the criteria, and after limiting the language to English, there were still 6,718 publications met the criteria for bibliometric analysis and visualization. The detailed flowchart of the publication screening process is shown in Figure 1. This study aligns with the Consolidated Criteria for Reporting Qualitative Research (COREQ) (16).

The visualization and bibliometric analysis of CRC ICB-related publications includes publication trends, country/region, institution/organization, including journals, authors, keywords, and distribution of major references. Based on the visualization we further performed a comprehensive analysis. In this study, CiteSpace (version 6.1) (17), VOSviewer (version 1.6.18) (18), SCImago Graphica (version 1.0.36), and the R (version 4.1) software package “bibliometrix” (https://www.bibliometrix.org↗) were used to perform the data analysis and visualization. Moreover, Microsoft Excel 2010 was used to quantitatively visualize the data. Specifically, the bibliometrix package was used to extract and visualize data on the distribution of the top 20 core authors and journals in the H-index. CiteSpace was used to extract and visualize the distribution of country/region, institution/organization, and author postings, as well as to include keyword citation burst analysis and co-citation network analysis. In addition, CiteSpace is used to calculate a node’s centrality, which quantifies the significance of a node’s position within a co-occurrence network. The most commonly used metric is betweenness centrality, and in this study, all references to centrality pertain specifically to betweenness centrality (19). This metric measures the percentage of shortest paths in the network that pass through a given node, helping to identify those nodes that play a critical role in maintaining the overall structure, facilitating information flow, and preserving connectivity (20). In this study, a high betweenness centrality value for a node generally indicates its significant influence within the research domain. SCImago Graphicay was used for country/region and author collaboration network mapping, and the rest of the co-occurrence and visualization analyses were performed using VOSviewer. With the use of these tools, we were able to extract key information from numerous publications and generate visual maps that provided valuable insights into our research (13, 21).

After inclusion and exclusion criteria, WoS obtained a total of 6,718 articles on ICB in CRC studies. Figure 2 illustrates the trend of publication numbers versus the average yearly citations from 2000 to 2022. The research on ICB in CRC has been growing rapidly. Especially over the last 5 years, the number of publications accounted for 67.12% of the total. The annual number of publications globally increased from 73 in 2000 to 1,501 in 2022. Before 2019, annual publications were below 500. However, post-2019, they significantly increased, maintaining a steady rise. The average number of citations per year for publications has increased each year and has been above 10 from 2017 to the present. Overall, these findings suggest that ICB research in CRC is experiencing rapid advancement, with increasing interest among researchers in exploring its application in CRC treatment.

As the third most common malignant tumor in the digestive tract globally, 40% of CRC cases are diagnosed at an early stage (34). While surgery remains the cornerstone of treatment for this disease, patients with disease recurrence and metastasis should undergo chemotherapy. Despite advances in treatment methods including targeted therapy, the prognosis for advanced CRC remains unfavorable (35). Increasing evidence suggests that blocking immune checkpoint molecules and activating anti-tumor immune responses is one of the most promising therapeutic approaches (36, 37).

In this era of information explosion, maintaining industry leadership and staying abreast of the latest research findings has become increasingly challenging (18). To showcase the current global scientific achievements in the field of ICB in CRC, we conducted a comprehensive search of literature related to this topic published in the WoSCC from the year 2000 to 2022. Ultimately, a comprehensive bibliometric analysis was conducted on 6,718 publications from 639 countries/regions. To the best of our knowledge, this is the first bibliometric study conducted specifically on ICB in the CRC field.

Over the past 20 years, we have observed a significant increase in the number of publications and citations related to ICB therapy in the field of CRC research. Post-2019, there has been an exponential surge in publications globally regarding ICB in CRC research. Our bibliometric analysis highlights this trend, underscoring the growing interest and evolving understanding in this research domain. Therefore, it is reasonable to assume that this field will enter a golden age in the coming years.

ICB therapies, such as the well-known PD-1 and PD-L1 therapies, as well as CTLA-4 therapy, have shown promising efficacy in improving CRC. However, not all CRC patients are suitable candidates for ICB treatment. Our analysis provides insights into the current status and potential future research hotspots of ICB therapy in the CRC field, aiding in identifying the current limitations in this area and offering a more comprehensive and objective academic perspective for researchers and investors.

The research findings indicate that China leads in terms of publication volume, while the USA is ahead in total citation counts and has the most productive authors, suggesting the critical roles played by both countries in advancing ICB therapy in CRC research. Additionally, countries such as Japan, Italy, Germany, and the UK have also made substantial contributions to the development of this field. It is noteworthy that among the top 10 institutions in terms of publication volume, 5 are from China, with the remaining 5 occupied by USA-based research institutions. However, the citation counts of articles from China are significantly lower than those from the USA. Equally important, the Chinese government has acknowledged this issue and has implemented several measures to improve the quality of academic publications. Regarding national/regional cooperation networks, the USA has established partnerships with numerous countries/regions globally, highlighting the extensive global impact of ICB therapy in CRC research.

Professor Thierry André from Sorbonne University in France is the most prolific author in terms of publications and holds key leadership roles in this field, focusing primarily on gastrointestinal malignancies. Additionally, he is a primary investigator in several phase I, II, and III clinical trials evaluating therapeutic agents for gastrointestinal malignancies. Professor Heinz-Josef Lenz from the University of Southern California Norris Comprehensive Cancer Center ranks second. Professor Lenz has been dedicated to developing innovative drugs for gastrointestinal malignancies in preclinical models and initiated the first prospective randomized phase II trial using FFPE specimen gene expression results. Moreover, he discovered that the primary tumor site in CRC is an independent prognostic indicator, now included in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines (NCCN guidelines).

Romain Cohen ranks third in terms of publication volume, also from Sorbonne University like Professor André. He is a core member of GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie), and interestingly, Professor André is the leader of this cooperative group. Professor Cohen’s research focuses on BRAFV600E mutation in metastatic CRC patients and the impact of microsatellite instability on stage III colon cancer patients. Regarding author collaboration networks, Professor André has established stable collaborations with several prolific authors, which contributes significantly to his high academic impact and underscores his important role in advancing this research field. His team’s articles are more likely to be published in top-tier journals.

In terms of journals, Table 4 lists the top 10 journals with the highest number of publications on this topic, as well as the top 10 journals with the highest total citations in this research field, which may represent the major journals for ICB research in CRC. Journals with high total citations generally have high quality, with 8 out of 10 having an IF higher than 10, including The New England Journal of Medicine (IF2023, 96.2), Nature Medicine (IF2023, 58.7), Nature (IF2023, 50.5), Science (IF2023, 44.7), Journal of Clinical Oncology (IF2023, 42.1), Clinical Cancer Research (IF2023, 10), Cancer Research (IF2023, 12.5), and PNAS (IF2023, 9.4). At the same time, we observed a positive co-citation relationship among both the top 10 journals in terms of publication volume and the top 10 journals in terms of total citations.

This co-citation relationship may reflect the interconnectedness and shared foundations of research within this field. Journals with higher total citations not only attract high-quality research but also become central hubs in the academic network, facilitating the dissemination and cross-referencing of key findings. The high impact factors of these journals suggest that they are platforms for cutting-edge research, which is often the most frequently cited due to its influence on subsequent studies. Moreover, these journals, particularly those like The New England Journal of Medicine, Nature Medicine, and Journal of Clinical Oncology, often publish studies with substantial clinical implications and translational potential, making them highly relevant to researchers and clinicians alike.

Co-cited literature refers to documents that are commonly cited together by multiple publications in a particular field. These articles typically address the characteristics, biological properties, classification, function, and important research mechanisms related to the study subject, often indicating groundbreaking or summarizing significance within the field (38). These co-cited papers form a “knowledge base” that underpins advancements in research. Table 5 lists the top 10 most cited papers, and the knowledge background and reported research results covered in these papers may hold significant importance for research on immune ICB in the field of CRC.

One of the foundational studies in this area is the work of Dung T. Le et al. (22), which evaluated the efficacy of PD-1 blockade in cancers with MMR. Their findings not only highlighted a subgroup of CRC that responds favorably to ICB but also pointed toward the integration of MMR testing as a potential biomarker for patient stratification. This connection between cancer genetics and immunotherapy established a crucial pathway for identifying patients most likely to benefit from these treatments, offering a targeted solution to the variability in response rates across different tumor types.

Michael J. Overman and colleagues advanced this understanding by showing that the combination of Nivolumab and Ipilimumab yielded superior outcomes in patients with dMMR/MSI-H metastatic CRC compared to monotherapy (23). Their work underscores the importance of combination therapies in enhancing efficacy and optimizing patient outcomes, particularly in challenging cases such as metastatic disease.

Another crucial element in CRC immunotherapy is the tumor immune microenvironment. Research by Nicolas J. Llosa et al. (25). provided key insights by linking MMR status with specific immune characteristics, such as elevated Th1/CTL immune activity. This association revealed why MSI tumors, despite having an active immune microenvironment, are not naturally cleared, suggesting that targeted immune checkpoint inhibition may offer selective benefits for these subtypes of CRC. Such findings lay the groundwork for personalizing treatment strategies based on the tumor’s immune and genetic profile.

Although PD-1 inhibitors have shown clinical benefits in MSI-H or dMMR tumors after treatment, the efficacy of PD-1 inhibitors compared to chemotherapy as first-line treatment for patients with MSI-H-dMMR advanced or metastatic CRC remains unclear. Therefore, Professor Thierry André and colleagues conducted a randomized, open-label phase 3 clinical trial, including a total of 307 treatment-naive MSI-H-dMMR metastatic CRC patients. After a 2-year follow-up, the median overall survival was 13.7 months in the pembrolizumab group and 10.8 months in the chemotherapy group. There were 56 deaths in the pembrolizumab group and 69 deaths in the chemotherapy group. The overall response rate was 43.8% in the pembrolizumab group and 33.1% in the chemotherapy group. Within the overall response rate, 83% of patients in the pembrolizumab group experienced ongoing remission compared to 35% in the chemotherapy group. Grade 3 or higher treatment-related adverse events occurred in 22% of the pembrolizumab group and 66% of the chemotherapy group. This pivotal trial not only provides clear evidence for the use of pembrolizumab in specific CRC populations but also highlights the potential to shift treatment paradigms away from traditional chemotherapy for these patients.

The role of the immune system in cancer prognosis has been acknowledged for over a century, but only in recent years has it started to influence clinical decision-making. The International Immuno-Oncology Society’s evaluation of the Immunoscore in CRC offers a refined tool for assessing recurrence risk based on immune infiltration, which could complement traditional TNM staging systems. This approach points to the need for integrating immune parameters into cancer classification systems, offering a more nuanced approach to predicting patient outcomes (28).

One of the remaining obstacles in ICB treatment is primary resistance (14). The groundbreaking study by Bertrand Routy et al. identified the gut microbiota as a key factor influencing the efficacy of PD-1 inhibitors. This discovery opens new avenues for enhancing ICB therapy by modulating the microbiome, offering potential solutions for patients who do not initially respond to treatment.

In summary, these highly cited studies form the core of CRC immunotherapy research, addressing both foundational concepts and emerging challenges. Their clinical significance is underscored by the fact that the majority are clinical trials, emphasizing the ongoing need to translate scientific discovery into practical solutions. By highlighting these pivotal works, our study seeks to provide researchers and clinicians with a deeper understanding of the evolving landscape of ICB in CRC and potential strategies for overcoming current limitations in treatment.

Keywords are emphasized and highlighted in an article to capture its core content. By analyzing these keywords, we can derive the evolving focus of research topics within this field (15). We analyzed keywords and burst terms. The results indicate significant thematic changes in the ICB’s role in CRC research over the past 20 years. The main trends are manifested in the following two aspects:

Our analysis highlights a clear progression in the development of ICB therapies, from early mechanistic studies to clinical applications. Initial research focused heavily on the molecular mechanisms underlying ICB, particularly with CTLA-4, and expanded to include in vivo experiments that evaluated the efficacy of new drugs. The rise in burst terms related to clinical trials reflects a significant transition toward testing ICB therapies in human subjects. The emergence of terms related to adverse events, such as immune-related adverse events (irAEs), underscores the growing attention to the safety and side effects associated with immunotherapy. This shift suggests that as ICB theories mature, the research focus has moved beyond basic efficacy studies to practical challenges in clinical implementation, such as optimizing treatment outcomes and minimizing adverse effects.

At a deeper level, this trend reveals the bottlenecks in the clinical application of ICB therapy. Although ICB has shown efficacy in advanced CRC patients, its effectiveness remains constrained by issues related to adverse reactions and the sustainability of therapeutic outcomes (39). Moreover, the integration of personalized medicine could help mitigate some of these challenges by identifying patients at higher risk for irAEs and adjusting treatment protocols accordingly. This proactive approach allows for better monitoring and management of potential side effects, enhancing the overall safety and effectiveness of treatment. Therefore, future research should not only focus on optimizing therapeutic efficacy but also emphasize a deeper understanding of the mechanisms underlying irAEs and how to predict and manage these reactions to achieve safer and more effective treatment.

In addition, this trend emphasizes the increasing importance of personalized medicine in tailoring ICB therapies to specific CRC subtypes. By leveraging genetic profiling and biomarker identification, researchers can better understand which patients are likely to respond positively to ICB treatment. For instance, the identification of specific mutations or immune signatures can guide clinicians in selecting appropriate candidates for ICB therapy, thereby enhancing treatment efficacy. Personalized medicine can also facilitate the development of stratified treatment plans, allowing healthcare providers to adjust ICB protocols based on individual tumor characteristics, such as immune microenvironment and tumor burden. Furthermore, it can improve treatment outcomes by enabling dose adjustments and combination therapies tailored to patients’ immune responses.

Another significant theme revealed by keyword analysis is the shift from broad-spectrum ICB treatments to precision medicine approaches. In the early stages, research primarily explored the general application of ICB in CRC. However, more recent studies have focused on stratifying patients based on genetic and molecular characteristics, particularly differentiating between mismatch repair-deficient (dMMR) and microsatellite instability-high (MSI-H) tumors. The advent of precision medicine has led to the identification of distinct CRC subtypes that respond differently to ICB therapies. Keyword trends indicate that the field has progressed from identifying these subtypes to designing targeted therapies and conducting clinical trials to validate their effectiveness. As the field continues to evolve, the integration of ICB therapy with genetic and molecular profiling represents a key advancement in personalized cancer treatment (40).

While ICB therapy demonstrates promising therapeutic effects in dMMR/MSI-H mCRC, its efficacy in other subtypes remains a topic of ongoing investigation (41). Particularly noteworthy is the fact that the majority of CRC patients fall into the pMMR or MSS subtype, suggesting potential limitations in the effectiveness of ICB therapy for this population (42). Consequently, researchers have redirected their focus toward understanding immune escape mechanisms in pMMR/MSS CRC. Further in-depth clinical research into the combined use of ICB and other treatment modalities may provide valuable therapeutic insights for patients with pMMR/non-MSI-H CRC (43).

Although ICB has demonstrated substantial potential in the treatment of CRC, keyword analysis has also highlighted several unresolved challenges. Firstly, the efficacy of ICB therapy remains largely confined to specific subtypes, such as dMMR/MSI-H, while the majority of CRC patients fall into the pMMR/MSS subtype (44). This necessitates a deeper investigation into the limitations of ICB therapy in this patient population and the mechanisms of immune escape. Secondly, the high incidence of irAEs further restricts the broad application of ICB therapy, emphasizing the need for research focused on balancing efficacy with safety.

In light of these challenges, future research should advance in several key areas: First, the identification of additional subtypes of patients who could benefit from ICB therapy through new molecular markers and bioinformatics technologies; second, the development of combination strategies with ICB, such as combined chemotherapy, targeted therapy, or novel immunomodulators, to address the efficacy limitations of ICB in pMMR/MSS CRC patients; and finally, enhancing the prediction, monitoring, and management of irAEs to minimize the occurrence of adverse reactions. These directions not only have the potential to advance CRC immunotherapy but also offer insights for the treatment of other types of cancers.

Clinical physicians have long prioritized enhancing clinical therapies for CRC and improving patient prognosis (45). With advances in tumor cell biology research, ICB has garnered significant attention in the treatment of malignant tumors, yielding notable efficacy in certain CRC subtypes. Despite numerous publications on ICB in the CRC domain, there has been no literature-based bibliometric analysis conducted in this area. This study delves into an in-depth analysis of the research direction and prospects of ICB in the CRC domain; however, it also has limitations. Firstly, the literature search was limited to the core dataset of the WOS, focusing solely on English-language publications, which may inherently bias our findings and potentially exclude relevant original works published in other languages. This bias can lead to an incomplete understanding of the global research landscape, particularly in regions where non-English publications are prevalent. Furthermore, the bibliometric analysis method employed is only applicable to general information and does not encompass full-text content, potentially resulting in the omission of crucial details such as author viewpoints and future perspectives. Additionally, our analysis predominantly featured highly cited papers, which, while reflecting significant contributions to the field, may overlook important studies that have not yet received widespread recognition. To address these limitations, future research endeavors will expand the scope of data collection, including non-English publications and lesser-cited studies, enhance discoverability, and provide more valuable insights and support for researchers.