Global research landscape and trends of immunotherapy in biliary tract cancers

To the Editor: Biliary tract cancer (BTC) is a malignant tumor originating from the epithelial cells of the bile ducts and is characterized by high malignancy and invasiveness. BTC can be classified into intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder carcinoma on the basis of its anatomical location, with ECC further divided into perihilar cholangiocarcinoma and distal cholangiocarcinoma.[1] While BTC remains rare, its global prevalence has shown an increasing trend.[2] The pathogenesis of BTC involves various pathophysiological processes, including genetic mutations, epigenomic dysregulation, microenvironmental remodeling, immune escape, and others.[3–5] In recent years, the use of immune checkpoint inhibitors (ICIs) has enabled significant breakthroughs in tumor therapy. Several studies have demonstrated that treatment regimens centered on ICIs can significantly prolong patient survival. In 2022, the TOPAZ-1 study (durvalumab in combination with gemcitabine and cisplatin) revealed that this ICI-based regimen significantly improved median overall survival (mOS) (12.8 months) in previously untreated patients with advanced BTC, overcoming the bottleneck of a mOS of less than 1 year for BTC.[6] In 2023, the larger sample size in the KEYNOTE-966 study (pembrolizumab in combination with a gemcitabine and cisplatin) similarly improved the mOS (12.7 months) in previously untreated patients with advanced BTC.[7] Consequently, immunotherapy combined with chemotherapy is the first-line regimen recommended by guidelines for advanced BTC. In addition to immunotherapy–chemotherapy combinations, alternative immunotherapeutic multimodal approaches incorporating targeted agents and locoregional therapy have demonstrated favorable efficacy and safety profiles in patients with BTC.[8] Bibliometric analysis, which is widely applied across medical research fields, is used to uncover emerging research hotspots and identify future development trends. In recent years, bibliometric analyses have been conducted to explore research advances in therapy for various cancer types (such as hepatocellular carcinoma), but such investigations remain scarce for BTC.[9] Therefore, in this study, a bibliometric analysis of the current status and progress of immunotherapy for advanced BTC was conducted. Publications related to immunotherapy in patients with BTC up to April 28, 2025, were searched in the Web of Science Core Collection (WoSCC) database. The detailed search strategy is included in the Supplementary Materials, https://links.lww.com/CM9/C821. After excluding non-article and non-English publications, as well as unrelated publications, a total of 410 publications were included in the analysis [Supplementary Figure 1, https://links.lww.com/CM9/C821]. VOSviewer v.1.6.20 (Leiden University, the Netherlands) is a software tool for exploring coauthorship and co-occurrence on the basis of data and presenting the map in three possible representations: (1) network, (2) overlay, or (3) density visualization. In our study, VOSviewer was used for analyzing the coauthorship of authors, countries, and keyword co-occurrence analysis. The R package “bibliometrix” was applied in this study to provide an overview of publication status; the number of annual publications, the number of publications by country, institution, author, or journal; and the frequency of keyword occurrence. This bibliometric analysis included 410 articles on BTC immunotherapy, authored by 3214 researchers across 165 journals. The number of annual publications consistently remained below five from 2012 to 2017. A marked increase began in 2018 (n = 7), surged to 24 in 2020, and increased to 76 by 2022, culminating in the peak productivity of 116 publications in 2024 [Supplementary Figure 2, https://links.lww.com/CM9/C821]. Seventeen countries and regions contributed to the body of publications, with China dominating the output (n = 262), followed by the United States (n = 42), Japan (n = 26), and South Korea (n = 25) [Supplementary Table 1, https://links.lww.com/CM9/C821]. The main reasons can be attributed to the higher incidence of BTC in Asia and the comprehensive and advanced medical technology system in the United States. In the coauthorship analysis, there was extensive collaboration between many countries/regions [Supplementary Figure 3A, https://links.lww.com/CM9/C821]. A total of 197 institutions contributed to the publications. Among the 197 contributing institutions, the top 10 were led exclusively by Asia organizations, with Fudan University (n = 42), the Chinese Academy of Medical Sciences and Peking Union Medical College (n = 35), and Sun Yat-sen University (n = 28) being the most productive [Supplementary Table 2, https://links.lww.com/CM9/C821]. A total of 3214 authors contributed to the publications. All the top 10 authors were Chinese-affiliated, led by Zhao HT (n = 20), Yang XB (n = 19), and Zhou J (n = 18) [Supplementary Table 3, https://links.lww.com/CM9/C821]. The coauthorship analysis revealed extensive and intricate cooperative relationships between authors, and an author collaboration network was generated to illustrate these contributions [Supplementary Figure 3B, https://links.lww.com/CM9/C821]. Among the top 10 institutions with the highest publication output in BTC immunotherapy research, eight institutions were from China, accounting for 80% of the leading contributors. Concurrently, the top 10 most prolific authors were affiliated with Chinese institutions, underscoring China’s dominant role in advancing this field. In recent years, Fudan University from China has held a leading position in terms of publication volume (n = 42). The team led by Zhou J and Fan J at Fudan University has concentrated on the molecular characterization and clinical investigation of BTC. The team established the triple regimen combining ICI–chemotherapy–lenvatinib, which demonstrated remarkable survival benefits with tolerable toxicity in unresectable ICC, advancing the progress of ICIs-based immunotherapeutic strategies in BTC management.[10] Additionally, the Chinese Academy of Medical Sciences and Peking Union Medical College ranked second in BTC immunotherapy research with 35 publications, and the main research team led by Zhao HT has made instrumental contributions to BTC immunotherapy clinical research. They focus primarily on evaluating combination regimens that integrate ICIs with systemic therapies (chemotherapy and targeted agents) and local–regional modalities (radiotherapy, hepatic arterial infusion chemotherapy, or transarterial chemoembolization) in patients with advanced BTC, and establish efficacy and safety profiles for first-line and subsequent-line treatments.[8] The articles were published in 165 different journals. Among the top 10 journals publishing the most articles on immunotherapy for BTC, 7 journals were classified as Journal Citation Reports (JCR) Q1 and the remaining 3 were classified as JCR Q2 [Supplementary Table 4, https://links.lww.com/CM9/C821]. Among the 781 screened keywords, 96 met the minimum occurrence threshold (≥3) and were subsequently clustered into 11 thematic groups through co-occurrence analysis [Supplementary Figure 3C, https://links.lww.com/CM9/C821]. Cluster 1 focused on immune cells that participate in antitumor immunity, primarily the terms “dendritic cell”, “macrophage”, and “T cell”. Clusters 2 focused on the combination therapies that integrate systemic therapy with immunotherapy, including “chemotherapy”, “targeted therapy”, “gemcitabine”, “anlotinib”, “apatinib”, and “bevacizumab”. Clusters 3–4 focused on evaluating the effectiveness and toxicity of immunotherapy for BTC, such as “overall survival”, “efficacy”, and “safety”. Clusters 5–7 and 10 focused on various ICIs agents, mainly including “immune checkpoint inhibitors”, “camrelizumab”, “nivolumab”, and “durvalumab”. Clusters 8–9 focused on immunotherapy biomarkers, primarily “programmed death-1 (PD-1)” and “programmed death-ligand 1 (PD-L1)”. Cluster 11 focused on combination therapies integrating local–regional therapy with immunotherapy, including “radiotherapy”. Temporal analysis of keyword evolution revealed a focus on phase transitions in research within the BTC immunotherapy domain [Supplementary Figure 3D, https://links.lww.com/CM9/C821]. Earlier BTC immunotherapy investigations focused on antitumor immunity mechanisms, as the most common terms included “tumor microenvironment”, “immune infiltration”, “immune checkpoint”, “PD-1”, “dendritic cell”, “T cell”, and “macrophages”. Subsequent research efforts prioritized the clinical validation of the therapeutic efficacy of immunotherapy for BTC, emphasizing various ICIs (“pembrolizumab” and “sintilimab”), combinatorial therapeutic strategies (“chemotherapy”, “targeted therapy”, “lenvatinib”, “anlotinib”, and “radiotherapy”), and clinical feasibility (“efficacy”, “safety”, and “overall survival”). Recently, studies have increasingly focused on predictive biomarkers and identification of responsive candidates (“machine learning”, “nomogram”, and “fibroblast growth factor receptor [FGFR]”). The most frequently occurring keyword terms associated with BTC immunotherapy included “immunotherapy”, “cholangiocarcinoma”, “biliary tract cancer”, “intrahepatic cholangiocarcinoma”, “prognosis”, “chemotherapy”, “lenvatinib”, “PD-L1”, and “immune checkpoint inhibitors” [Supplementary Figure 4, https://links.lww.com/CM9/C821]. A three-field plot further demonstrated the associations of keywords with authors and journals in the field of immunotherapy in BTC research [Supplementary Figure 5, https://links.lww.com/CM9/C821]. The 30 most highly cited papers on immunotherapy for BTC were identified on the basis of their citations in the WoSCC. Among these publications, clinical studies investigating BTC immunotherapy constituted the predominant category (n = 21), with the remaining six articles focusing on molecular mechanisms and molecular characteristics and three articles focusing on biomarkers for immunotherapy [Supplementary Table 5, https://links.lww.com/CM9/C821]. Among the 21 clinical studies on BTC immunotherapy, immunotherapeutic approaches have focused predominantly on ICIs (n = 14). Analysis of the 30 most highly cited publications revealed diverse immunotherapy approaches for BTC: three phase II trials evaluated ICIs monotherapy, whereas phase II dual ICI trial and two phase I dual pathway inhibitors (targeting PD-1 and vascular endothelial growth factor receptor [VEGFR-2], and targeting PD-L1 and transforming growth factor-beta [TGF-β]) study demonstrated clinical efficacy. The dominant focus was ICIs–chemotherapy combinations (5 studies), establishing this combination for advanced BTC. Three studies reported favorable outcomes with ICIs-targeted therapy, and one phase II trial achieved promising results using triple-modality therapy (ICI/chemotherapy/targeted agents). Pembrolizumab emerged as the dominant research focus in BTC immunotherapy, as evidenced by its representation in all three top-cited KEYNOTE trials and 28.6% (4/14) of clinical ICI studies. Research on cellular immunotherapy, which primarily comprises chimeric antigen receptor (CAR)-T cell therapy and cellular vaccines, remains relatively limited compared with that of multi-ICI combination studies for BTC, as evidenced by only five studies among the 30 most-cited articles. The efficacy and safety of cellular immunotherapy for BTC require further validation through large-scale studies. Among the top 30-cited publications, six studies on molecular mechanisms and molecular characteristics studies established foundational frameworks for optimizing immunotherapy. Concurrently, three biomarker investigations leveraged used gut microbiome, genomic, and immunohistochemical analyses to identify responsive patient populations. However, this study has several limitations. First, although comprehensive keyword searches were conducted, our exclusive reliance on the WoSCC may have omitted relevant literature from databases such as PubMed or Scopus. Second, as immunotherapy is an emerging field, recently published studies lack sufficient citation accumulation time, potentially resulting in length–time bias that underestimates the impact of newer publications. In conclusion, the field of BTC immunotherapy has witnessed expanding interest, as evidenced by marked growth in annual publication output, underscoring its emerging prominence in oncology research. In this bibliometric study, 410 publications were analyzed to systematically map the developmental landscape of BTC immunotherapy, and pivotal contributing countries, institutions, authors, and seminal publications spanning the last decade were identified. Currently, clinical research on BTC immunotherapy represents the most prominent research focus, especially studies evaluating ICI-centric therapeutic regimens. Moreover, molecular mechanistic studies identifying novel immune therapeutic targets and predictive biomarkers for treatment response may constitute the most promising research frontier. In addition, symptomatic treatment and comprehensive management of immune-related adverse events are essential throughout the immunotherapy. These findings provide new researchers with a comprehensive overview of BTC immunotherapy and offer valuable insights for guiding future research directions. Funding This work was supported by grants from the CAMS Innovation Fund for Medical Sciences (CIFMS) (Nos. 2022-I2M-C&T-A-003, 2021-I2M-1-061, and 2021-I2M-1-003). Conflicts of interest None.