Global research trends in fecal microbiota transplantation combined with immune checkpoint inhibitors for cancer immunotherapy: a bibliometric analysis

Abstract

Background

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by restoring antitumor immune responses. However, heterogeneous efficacy, primary or acquired resistance, and immune-related adverse events (irAEs) remain major clinical challenges. There is evidence that gut microbiota critically regulate ICI efficacy, and fecal microbiota transplantation (FMT) has emerged as a promising intervention to improve therapeutic outcomes. Here, we performed a bibliometric analysis to map global research trends, hotspots, and frontiers in FMT combined with ICIs for cancer immunotherapy.

Methods

A range of scientometric tools, including CiteSpace, VOSviewer, Bibliometrix R package, and Tableau, were employed to retrieve and analyze the literature on FMT combined with ICIs for cancer immunotherapy from the Web of Science Core Collection for the period from 2015 to 2026. The analyses covered national and institutional collaboration networks, the identification of highly productive authors, journal impact and publication trends, co-cited reference analysis, as well as keyword co-occurrence, clustering, and burst detection.

Results

A total of 345 relevant publications were identified, with annual output rising rapidly since 2019 and reaching a peak in 2025. China ranked first in publication volume, while the United States showed the highest centrality in international collaboration. The leading research institutions were the University of Texas MD Anderson Cancer Center, Shanghai Jiao Tong University, and Université Paris-Saclay. Routy, Bertrand and Wang, Yinghong were prominent high-impact authors. Co-citation and keyword analyses revealed a shift in research focus from gut microbiota-mediated regulation of ICI efficacy to clinical translation of FMT for reversing resistance, and further to mechanistic insights into microbial metabolites and the tumor microenvironment (TME). Further keyword analysis demonstrated that FMT research has expanded to digestive system malignancies, including colorectal, gastric, and hepatocellular carcinomas (HCCs). Current research hotspots include “dysbiosis”, “dietary fiber”, “chain fatty acids”, “tumor microenvironment”, “consensus statement”, and “international scientific association”.

Conclusions

This bibliometric analysis reveals that the research field of FMT combined with ICIs has evolved from descriptive correlations to mechanism-driven research, with an expanding focus on digestive system tumors. Future research should prioritize large-scale randomized controlled trials (RCTs) and standardized clinical protocols, underpinned by in-depth mechanistic studies, to advance microbiome-based precision cancer immunotherapy.

Highlight box.

Key findings

• Research on fecal microbiota transplantation (FMT) combined with immune checkpoint inhibitors (ICIs) in cancer immunotherapy has grown rapidly since 2019, peaking at 92 articles in 2025.

• China leads globally in publication volume (137 articles), while the United States exhibits the highest centrality (0.53), serving as a key hub for international collaboration.

• Research hotspots have shifted from “gut microbiota-mediated regulation of ICI efficacy” to “FMT reversal of resistance”, and further to “microbial metabolites” and “tumor microenvironment” modulation.

• The scope of tumor types has expanded from melanoma and non-small cell lung cancer to digestive system malignancies, including colorectal, gastric, and hepatocellular carcinomas (HCCs).

What is known and what is new?

• It is well established that gut microbiota composition critically influences ICI efficacy, and FMT can remodel the microbiota to enhance antitumor immunity.

• This study provides the first focused bibliometric mapping of FMT combined with ICIs in cancer immunotherapy. It reveals a three-stage thematic evolution from foundational correlation to clinical translation, and finally to mechanistic deepening and standardization. The study also identifies emerging frontiers, including “dysbiosis”, “dietary fiber”, “chain fatty acids”, “tumor microenvironment”, “consensus statement”, and “international scientific association”, with digestive system tumors (colorectal cancer, gastric cancer and HCC) emerging as a rising hotspot.

What is the implication, and what should change now?

• Future research should prioritize large-scale randomized controlled trials and standardized FMT protocols.

• A multidimensional donor-recipient matching system integrating metagenomics, metabolomics, immunology, and artificial intelligence is urgently needed.

• Strengthened international collaboration and harmonized clinical guidelines are essential to advance microbiome-based precision cancer immunotherapy from concept to clinical practice.

Introduction

Immunotherapy has revolutionized modern oncology, with immune checkpoint inhibitors (ICIs) emerging as key treatments for a broad range of advanced malignancies (1,2). ICIs, including monoclonal antibodies targeting programmed cell death protein 1 (PD-1; e.g., pembrolizumab and nivolumab)/programmed death ligand 1 (PD-L1; e.g., atezolizumab and durvalumab) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4; e.g., ipilimumab and tremelimumab), reinvigorate antitumor immune surveillance by blocking key pathways exploited by tumor cells to evade immune attack. By eliminating immunosuppressive signals, ICIs restore the cytotoxic function of T cells (2,3). To date, ICIs have demonstrated remarkable clinical efficacy across various cancer types, including melanoma (4), non-small cell lung cancer (NSCLC) (5) and renal cell carcinoma (6). However, substantial interindividual heterogeneity in treatment response persists, driven by factors such as the tumor microenvironment (TME), tumor heterogeneity, and host-related characteristics (7). ICIs also face several challenges, particularly primary or acquired resistance and immune-related adverse events (irAEs) (8,9). Accordingly, enhancing ICI efficacy while reducing toxicity is now a major priority in cancer immunotherapy research.

The gut microbiota is now recognized as a key modulator of antitumor immune responses. Its composition and diversity critically determine clinical responses to ICIs, with specific species playing pivotal roles. Beneficial bacteria such as Akkermansia muciniphila and Ruminococcaceae (10,11), promote ICI responses, whereas species like Enterocloster spp. correlate with diminished efficacy (12). Given this pivotal role, reshaping the microbiota to enhance antitumor immunity has become a promising therapeutic strategy. Fecal microbiota transplantation (FMT), a direct and comprehensive intervention involving the transfer of fecal microbiota from a healthy donor into a patient’s intestinal tract to restore a functional gut microbial community, has garnered increasing attention. FMT has been utilized not only for recurrent Clostridioides difficile infection, inflammatory bowel disease, and irritable bowel syndrome but also, more recently, for metabolic disorders, neurological conditions, and in cancer treatment (13,14). Multiple clinical trials now indicate that the combination of FMT with ICIs markedly improves responses and alleviates irAEs in solid tumor patients (15). Preliminary findings from phase I/II clinical trials have confirmed the safety and potential efficacy of FMT combined with ICIs in patients with melanoma and NSCLC (16,17). A recent multicenter, open-label phase II trial reported an objective response rate (ORR) of 80% (16/20) for FMT plus anti-PD-1 in patients with NSCLC and 75% (15/20) for FMT plus dual checkpoint blockade (anti-PD-1 plus anti-CTLA-4) in patients with melanoma, underscoring the clinical activity of FMT-based combination strategies (17). A meta-analysis of 164 patients with solid tumors reported a pooled ORR of 43% [95% confidence interval (CI): 0.35–0.51] for FMT combined with ICIs, rising to 60% in the subgroup receiving concurrent anti-PD-1 and anti-CTLA-4 therapy (18). However, results are variable, one trial in anti-PD-1-refractory solid tumors showed an ORR of only 7.7% (19). The variability likely reflects differences in donor selection criteria, recipient characteristics (such as tumor type, prior treatment history, and immune status), administration protocols, and microbiota composition (20). FMT also has unresolved challenges, such as standardization, successful engraftment of transplanted microbiota in the gut or TME, risk of ecological perturbation, and lack of synergistic interactions among the microbial communities (21). Moreover, how FMT modulates immune cell function, influences the TME, and interacts with ICIs remains poorly understood. All of this demands further, in-depth investigation.

Given the ongoing challenges and uncertainty, a comprehensive appraisal of FMT and ICIs in tumor immunotherapy is urgently needed to synthesize existing evidence and outline future research priorities. Conventional reviews in this area are often constrained by inherent subjectivity. Bibliometrics, a quantitative method that applies mathematical and statistical techniques to analyze publication characteristics, enables visualization of scientific knowledge maps (22). However, a systematic quantitative analysis of FMT combined with ICIs remains lacking. Accordingly, this study employs bibliometric analysis to delineate research hotspots, trends, and future directions, offering valuable insights for researchers and clinicians engaged in cancer immunotherapy and microbiome-related studies. We present this article in accordance with the BIBLIO reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1404/rc).

Methods

Data acquisition

The data for this study were retrieved from the Web of Science Core Collection, a multidisciplinary database recognized for its extensive citation indexing. All publications relevant to the research field were retrieved from January 1, 2015, to March 11, 2026. The search strategy employed during this period consisted of the following term combinations: TS = [((“fecal” OR “intestinal” OR “gut” OR “donor”) AND (“microbiota” OR “microbiome” OR “microbe” OR “bacterial” OR “feces” OR “microflora” OR “flora”) AND (“transplantation” OR “transfer” OR “transplant” OR “infusion”)) OR FMT OR “fecal-transplantation” OR “fecal-transplant” OR “bacteriotherapy”] for fecal microbiota transplantation; TS = (“immune checkpoint inhibitors” OR “immune checkpoint inhibitor” OR “immune checkpoint blockade” OR “immunological checkpoint inhibitors” OR “immunological checkpoint inhibitor” OR “immuno-checkpoint inhibitors” OR “immune checkpoint blockers” OR “anti-PD-1” OR “anti-PD-L1” OR “antiCTLA-4” OR “Ipilimumab” OR “Tremelimumab” OR “Pembrolizumab” OR “Atezolizumab” OR ICIs) for immune checkpoint inhibitors; TS = (“cancer” OR “tumor” OR “tumour” OR “neoplasm*” OR “oncology”) for cancer; and TS = (“immunotherap*” OR “immune checkpoint inhibitor*” OR “anti-PD-1” OR “anti-PD-L1” OR “anti-CTLA-4” OR “checkpoint blockade”) for immunotherapy. The following criteria were applied for further screening: (I) publications were restricted to English; and (II) only articles and reviews were considered, whereas conference abstracts, case reports, letters, early access publications, book chapters, and publications with expression of concern were excluded. The complete screening process is illustrated in Figure 1. Data retrieval, screening, and extraction were independently performed by two authors, with cross-verification performed between them; any disagreements were resolved by consulting a third author. A total of 345 eligible publications, including full records and cited references, were identified and exported in plain text format.

Figure 1.

A flow chart of the retrieval process in this study. #1, FMT-related terms; #2, ICI-related terms; #3, cancer-related terms; #4, immunotherapy-related terms. FMT, fecal microbiota transplantation; ICI, immune checkpoint inhibitor.

Bibliometric analysis tools and methods

This study used bibliometric methods to analyze the research frontiers and hotspots of FMT combined with ICIs for tumor immunotherapy. Data management and analyses were performed using VOSviewer (v1.6.20), CiteSpace (v6.4.R1), R software (v4.4.1), Tableau (2024.3.0), and Microsoft Excel. International collaboration networks were mapped using Tableau, and VOSviewer was employed to visualize highly co-cited references and keyword co-occurrence patterns. CiteSpace enabled a detailed visualization of institutions, authors and keywords. R software was used to generate national publication trends and international collaboration patterns. Microsoft Excel was used for data management, annual publication statistics, and table generation. By employing this integrated approach, the analytical precision and visual clarity of the findings are substantially improved. The research workflow is presented in Figure 1.

Results

Annual volume and trends in publications

To comprehensively assess trends in the development of combining FMT with ICIs for tumor immunotherapy, we analyzed the annual publication output in this field from 2015 to 2026 (Figure 2A). The sustained growth in publication output reflects considerable research interest and notable advances in this area. As shown in the publication trend graph, the number of articles increased from 1 in 2015 to 5 in 2018; this modest output indicates that the field was still niche. From 2019, there was a marked rise in publications, largely driven by clinical evidence demonstrating that gut microbiota significantly influences the efficacy of ICIs and participates in modulating immune responses (23). Against this background, FMT emerged as a novel microbiota-based intervention capable of recolonizing dysregulated gut flora and improving immunotherapy outcomes. Following 2020, growing global interest in personalized and precision medicine further positioned FMT as a key microbiota-targeted strategy, transforming it into a research hotspot. Consequently, publication volume in this area increased, with a notable surge to 48 articles in 2022, ultimately reaching a peak of 92 articles in 2025. As of 2026, 27 articles have already been recorded. With the rapid clinical translation of FMT-based combination strategies, annual publication volume is expected to continue rising.

Figure 2.

Global publication trends and geographical distribution of FMT combined with ICI research in cancer immunotherapy. (A) Annual publication count and total cumulative publications. (B) National visualization network map. FMT, fecal microbiota transplantation; ICI, immune checkpoint inhibitor.

Analysis of trends and collaborations of countries, institutions, and authors

On the topic of FMT combined with ICIs for cancer immunotherapy (Table 1), China leads globally in publication counts (137 articles), which highlights its dominant output and sustained research commitment. The United States follows closely (91 articles) and ranks first in centrality (0.53), underscoring its pivotal role as a global collaborative hub and its extensive academic influence. Notably, India, while ranking eighth in output, holds a considerable centrality (0.17), indicating the significant value of its research within international networks. Geographically, research activity is concentrated in North America, Europe, and Asia (Figure 2B). Analysis of temporal trends (Figure 3A) reveals that the United States and France were early leaders, with the United States maintaining robust growth and surpassing France after 2020. China’s output, while lower initially, accelerated after 2021, propelling it to the lead position by 2024. The collaboration pattern analysis (Figure 3B) distinguishes between single-country (SCP) and multiple-country publications (MCP). China’s notable SCP involvement indicates a strong, self-sufficient domestic research capacity. In contrast, the United States excels in MCP, reflecting its deep integration into global collaborative networks. Similarly, high MCP ratios in Canada and France point to their active international research partnerships.

Table 1. Top 10 most productive countries.

Rank	Countries	Publications	Centrality	Area
1	China	137	0.03	Asia
2	United States	91	0.53	North America
3	Italy	28	0.10	Europe
4	Canada	24	0.09	North America
5	France	20	0.07	Europe
6	Iran	13	0.05	Asia
7	Japan	11	0.00	Asia
8	India	10	0.17	Asia
9	Germany	9	0.05	Europe
10	Sweden	9	0.07	Europe

Figure 3.

National publication trends and international collaboration status. (A) Line graph of national publications. (B) SCP (reflects domestic collaboration or academic self-sufficiency) and MCP (reflects international collaboration intensity) for the 20 most productive countries. MCP, multiple-country publications; SCP, single-country publications.

We analyzed the top 10 research institutions working on FMT combined with ICIs for cancer immunotherapy by publication output (Table 2), along with their centrality and their collaborating countries. The results reveal that numerous institutions worldwide have made significant contributions. The University of Texas MD Anderson Cancer Center in the United States leads in publication output (25 articles), followed by Shanghai Jiao Tong University (17 articles), as the leading contributor from China. While the Chinese Academy of Medical Sciences and Fudan University rank lower in output, they possess the highest centrality (0.23) of all institutions (Table S1). This suggests that these institutions play important connective roles within the global research network. French institutions also demonstrate notable performance, with Université Paris-Saclay and Georges Pompidou European Hospital ranking third and fourth in publication output, respectively. The scientific collaboration network generated by CiteSpace software reveals distinct patterns of institutional cooperation (Figure 4A). Three primary clusters are evident; the first is centered around the University of Texas MD Anderson Cancer Center, the second is dominated by Shanghai Jiao Tong University, and the third is led by Université Paris-Saclay, which indicates their substantial research influence and output in this field. However, the linkages between these three major clusters appear relatively limited, suggesting that international cooperation in this domain displays a clear pattern of regional clustering.

Table 2. Top 10 most productive institutions.

Rank	Institutions	Publications	Centrality	Country
1	University of Texas MD Anderson Cancer Center	25	0.06	United States
2	Shanghai Jiao Tong University	17	0.08	China
3	Université Paris-Saclay	11	0.01	France
4	Georges Pompidou European Hospital (HEGP)	10	0.05	France
5	Huazhong University of Science and Technology	10	0.10	China
6	Memorial Sloan Kettering Cancer Center (MSKCC)	8	0.03	United States
7	Centre Hospitalier de l’Université de Montréal (CHUM)	7	0.11	Canada
8	McGill University	7	0.01	Canada
9	Harvard Medical School	7	0.06	United States
10	Sun Yat-sen University	7	0.07	China

Figure 4.

Institutional and core author collaboration networks. (A) The main collaboration network of institutions. (B) The collaboration network of core authors.

Analysis of the leading authors in this field highlights key contributors and collaborative patterns (Table 3). Routy, Bertrand and Wang, Yinghong have each made pivotal contributions, with 10 publications each, establishing their leadership in the field. Elkrief, Arielle has published 9 articles, while Kroemer, Guido and Zitvogel, Laurence have each published 8 articles. Routy, Bertrand and Wang, Yinghong have been active since 2018, whereas Davar, Diwakar [2021] and Fang, Jingyuan [2023] appeared more recently, suggesting their emerging engagement in this evolving domain. The author collaboration network generated by CiteSpace (Figure 4B) visually delineates these research relationships. Prominent researchers, such as Routy, Bertrand, Wang, Yinghong, and Elkrief, Arielle, are represented by larger nodes, reflecting their substantial output and influence. The network metrics, with 939 nodes and 2,572 edges, reveal that the number of connections exceeds the number of individual authors, indicating a high degree of collaboration overall. This pattern suggests that co-authored, team-based publications are more prevalent than those produced by independent authors, highlighting a cooperative research landscape.

Table 3. Top 10 authors with the highest publication output.

Rank	Authors	Year	Papers
1	Routy, Bertrand	2018	10
2	Wang, Yinghong	2018	10
3	Elkrief, Arielle	2019	9
4	Kroemer, Guido	2018	8
5	Zitvogel, Laurence	2018	8
6	Derosa, Lisa	2018	7
7	Fang, Jingyuan	2023	6
8	Wargo, Jennifer A	2018	5
9	Abu-Sbeih, Hamzah	2018	4
10	Davar, Diwakar	2021	4

Analysis of journals

The top 10 journals by publication output on FMT combined with ICIs in cancer immunotherapy are listed in Table 4. Journal citation reports (JCR) and impact factors (IF) serve as key indicators of academic quality and influence, and the latest data for these 10 journals was retrieved from the Web of Science. Ranked by publication volume, the top five journals are Frontiers in Immunology (22 articles), Cancers (18 articles), Seminars in Cancer Biology (8 articles), Critical Reviews in Oncology/Hematology (7 articles), and Frontiers in Oncology (7 articles). Among these, Seminars in Cancer Biology holds the highest IF at 15.7, reflecting its significant role in publishing high-impact mechanistic and translational research. Frontiers in Immunology follows with an IF of 5.9, underscoring its prominence in immunology research relevant to cancer therapy. The prominence of these journals reflects the convergence of immunology, oncology, and microbiology in advancing combined microbiome-ICI therapies, and their robust publication records signal sustained interest and a growing knowledge base in this translational field. Beyond publication volume, citation impact further identifies leading journals in this area. As shown in Table 5, Science leads in total citations with 317 citations and an IF of 45.8, indicating its significant influence in the field, followed by Nature Medicine and Nature. All these journals are classified as Q1, highlighting their academic leadership in their fields.

Table 4. Top 10 journals with the most publications.

Rank	Journal	Articles	IF	JCR
1	Frontiers in Immunology	22	5.9	Q1
2	Cancers	18	4.4	Q2
3	Seminars in Cancer Biology	8	15.7	Q1
4	Critical Reviews in Oncology/Hematology	7	5.6	Q1
5	Frontiers in Oncology	7	3.3	Q2
6	International Journal of Molecular Sciences	6	4.9	Q1
7	Journal for Immunotherapy of Cancer	6	10.6	Q1
8	Ebiomedicine	5	10.8	Q1
9	Gut Microbes	5	11	Q1
10	Science	5	45.8	Q1

IF, impact factor; JCR, journal citation reports.

Table 5. Top 10 most co-cited journals.

Rank	Journal	Co-citations	IF	JCR
1	Science	317	45.8	Q1
2	Nature Medicine	270	50	Q1
3	Nature	260	48.5	Q1
4	Cell	244	42.5	Q1
5	Nature Communications	241	15.7	Q1
6	Annals of Oncology	225	65.4	Q1
7	New England Journal of Medicine	222	78.5	Q1
8	Gut	221	25.8	Q1
9	Frontiers in Immunology	221	5.9	Q1
10	Journal of Clinical Oncology	204	41.9	Q1

IF, impact factor; JCR, journal citation reports.

The dual-map overlay of journals delineates the linkages between citing and cited publications, elucidating knowledge flow in the research arena of FMT and ICIs in cancer immunotherapy. In this visualization, the left and right sides denote the disciplinary domains of citing and cited journals, respectively, where each data point corresponds to a journal and colored curves signify distinct citation routes. As depicted in Figure 5, two primary citation trajectories are identified: the green curve (z=3.6667476, f=4,342) and the orange curve (z=3.3460667, f=4,000). These pathways indicate that journals specializing in molecular biology and genetics serve as foundational sources for citations by publications in the fields of medicine, clinical research, and immunology, highlighting a pivotal cross-disciplinary knowledge transfer in this area of therapeutic research.

Figure 5.

Dual map of journals: colored tracks indicate citation links, with citing journals on the left and cited journals on the right.

Analysis of co-cited references

Co-cited references refer to references frequently cited together by researchers. In the co-citation network generated by VOSviewer, each node represents an individual reference or author, and its size corresponds to the frequency of citations; the links between nodes indicate co-citation relationships. In the VOSviewer analysis (Figure 6), the node corresponding to Routy et al. is the largest, which signifies its considerable academic influence and high citation frequency in the field (10). This landmark research revealed that FMT from patients with favorable responses to anti-PD-1 therapy into germ-free mice remarkably improved the antitumor efficacy of PD-1 blockade. Moreover, supplementation with Akkermansia muciniphila was found to restore therapeutic responses in certain non-responding patients. As one of the first studies to confirm that the gut microbiota can directly regulate the efficacy of PD-1 blockade in epithelial tumors, this work provided novel targets for clinical intervention. Another large node represented Gopalakrishnan et al.’s critical research, which demonstrated a significant association between gut microbiota diversity and clinical response to anti-PD-1 immunotherapy in melanoma patients (11). Collectively, these two studies provided essential experimental and theoretical support for the application of FMT in optimizing cancer immunotherapy. In addition, the top 10 most co-cited references are listed in Table 6. Each of these references has a co-citation count of at least 90, and they were primarily published in Science between 2015 and 2021, reflecting the extensive impact and academic significance of these works in the field.

Figure 6.

Visualization of a clustering map of co-cited references.

Table 6. Top 10 most co-cited references.

Rank	Author	Journal	DOI	Citations	Year
1	Routy, Bertrand	Science	10.1126/science.aan3706	240	2018
2	Gopalakrishnan, Vancheswaran	Science	10.1126/science.aan4236	224	2018
3	Matson, Vyara	Science	10.1126/science.aao3290	197	2018
4	Vétizou, Marie	Science	10.1126/science.aad1329	194	2015
5	Sivan, Ayelet	Science	10.1126/science.aac4255	180	2015
6	Baruch, Erez N.	Science	10.1126/science.abb5920	173	2021
7	Davar, Diwakar	Science	10.1126/science.abf3363	162	2021
8	Chaput, Nathalie	Annals of Oncology	10.1093/annonc/mdx108	114	2017
9	Mager, Lukas F.	Science	10.1126/science.abc3421	102	2020
10	Wang, Yinghong	Nature Medicine	10.1038/s41591-018-0238-9	91	2018

The co-citation network (Figure 6) shows that highly cited publications are primarily clustered in three research themes. The green cluster focuses on the fundamental mechanisms underlying the regulation of immunotherapy efficacy by gut microbiota. Landmark studies within this cluster confirmed the causal relationship between commensal bacteria and host antitumor immune activation (11,24), demonstrated the impact of gut microbiota on tumor-infiltrating lymphocytes (TILs) (10), and identified key signaling pathways involved in microbiota-immune crosstalk (25). These studies established the core theory that gut microbiota can influence the efficacy of ICIs, providing an essential theoretical basis for subsequent microbiota-targeted interventions. The red cluster centers on the clinical translation of FMT to enhance the efficacy of ICIs. Representative studies evaluated the therapeutic efficacy of FMT in immunotherapy-refractory tumors (26), verified its ability to reverse anti-PD-1 resistance via microbial reconstruction (16), and assessed its safety and feasibility in patients with advanced cancer (27). A seminal clinical trial by Davar et al. showed that FMT could restore anti-PD-1 responsiveness in patients with resistant melanoma, establishing FMT as a promising strategy to overcome immunotherapy resistance (26). The high citation frequency of this work underscores the importance of FMT in rebuilding antitumor immunity and reversing therapeutic resistance. The blue cluster highlights multi-omics and metabolic mechanisms that link gut microbiota to systemic antitumor immunity. Research in this cluster focused on microbial metabolites such as bile acids and short-chain fatty acids (SCFAs) as key mediators of immune regulation, identified specific microbial and metabolic signatures associated with ICI response, and dissected the molecular pathways through which metabolites modulate T-cell function and the TME (28). These studies revealed the functional mechanisms beyond microbial composition, providing precise targets for the development of precision microbiome-based immunotherapy.

Analysis of keyword co-occurrence, clustering, and burst

In our analysis of FMT combined with ICIs for tumor immunotherapy, we performed a frequency analysis of keywords, yielding the top 10 most frequently occurring terms, as presented in Table 7. This table revealed that “immunotherapy”, “gut microbiota” and “immune checkpoint inhibitors” ranked highest. This underscores the established prominence of gut microbiota-ICI combination therapy as a central research direction in cancer immunotherapy. The frequent mention of terms such as “efficacy”, “resistance”, and “therapy” reflects the field’s focus on therapeutic outcomes and the challenge of treatment resistance. Furthermore, “bacteria” exhibited the highest centrality, emphasizing its connective role, followed by “cancer”, “antitumor immunity”, “colorectal cancer”, “melanoma”, “ipilimumab”, “intestinal microbiota”, “metabolites”, “Fusobacterium nucleatum”, and “CTLA-4 blockade”. Colorectal cancer (CRC) and melanoma serve as the primary tumor types in this field. Among emerging mechanistic hotspots, microbial metabolites represent a key research focus. As visualized in Figure 7, these keywords link gut microbiota, ICIs, and cancer to other research areas.

Table 7. Top 10 keywords by frequency and centrality in this field.

Rank	Keywords	Frequency	Keywords	Centrality
1	Immunotherapy	164	Bacteria	0.54
2	Gut microbiota	128	Cancer	0.43
3	Immune checkpoint inhibitors	100	Antitumor immunity	0.38
4	Cancer	98	Colorectal cancer	0.31
5	Efficacy	77	Melanoma	0.29
6	Gut microbiome	74	Ipilimumab	0.28
7	Resistance	72	Intestinal microbiota	0.22
8	Fecal microbiota transplantation	71	Metabolites	0.19
9	Therapy	67	Fusobacterium nucleatum	0.17
10	Probiotics	59	Ctla 4 blockade	0.17

Figure 7.

Keyword co-occurrence map of FMT combined with ICIs for tumor immunotherapy. FMT, fecal microbiota transplantation; ICI, immune checkpoint inhibitor.

To identify research frontiers concerning FMT and ICIs in cancer immunotherapy since 2015, we employed CiteSpace to perform a cluster analysis of associated keywords (Figure 8A,8B). Cluster #0 is labeled “pd-l1”, followed by Cluster #1, labeled “immune checkpoint inhibitors”, Cluster #2 “fecal microbiota transplantation”, Cluster #3 “immune checkpoint blockade”, Cluster #4 “akkermansia muciniphila”, Cluster #5 “cancer treatment”, Cluster #6 “anti pd 1 efficacy”, Cluster #7 “efficacy”, Cluster #8 “gastric cancer”, Cluster #9 “screening tests”, and Cluster #10 “hepatocellular carcinoma”. These clusters reveal the predominant research themes since 2015. Core clusters such as “pd-l1”, “fecal microbiota transplantation” and “immune checkpoint inhibitors”, show sustained high activity, reflecting the ongoing need to overcome immunotherapy resistance. The emergence of cancer-specific clusters for gastric cancer (GC) and hepatocellular carcinoma (HCC) suggests the potential of FMT combined with ICIs in digestive system malignancies. The growing importance of “screening tests” clusters reflects a shift toward personalized therapeutic strategies.

Figure 8.

Keywords cluster analysis and timeline evolution. (A) Keywords Cluster analysis map. (B) CiteSpace visualization map of timeline view.

Keyword bursts capture the sharp increase in research activity over time, potentially signaling emerging future directions. Figure 9 presents the 25 keywords with the strongest bursts in this field. “Melanoma”, the first cancer type in which immunotherapy achieved a breakthrough, exhibits a burst strength of 2.99 and the longest burst duration, spanning from 2015 to 2021. “Nivolumab” shows the highest burst strength of 4.93, underscoring the crucial role of this PD-1 inhibitor in FMT combined with ICIs for cancer immunotherapy. Based on the analysis of keyword bursts and temporal changes of keyword clustering, the research focus on combining FMT with ICIs for cancer immunotherapy has evolved through three progressive stages, reflecting a clear evolution from foundational exploration to clinical application, and finally, mechanistic understanding and standardization. The initial foundational stage [2015–2019] was characterized by keywords such as “melanoma”, “CTLA-4 blockade”, “intestinal microbiota”, and “breast cancer”, during which research established the basic links between gut microbiota and ICI efficacy. Supported by clustering timeline results, three clusters (#1 “immune checkpoint inhibitors”, #3 “immune checkpoint blockade”, #7 “efficacy”) were prominent in this early period, while secondary clusters #0 (“pd-l1”) and #4 (“akkermansia muciniphila”) existed as supplementary subtopics and gained attention after 2018. This was followed by a clinical translation phase [2020–2024], marked by a surge in terms including “nivolumab”, “ipilimumab”, “fecal microbiota transplant”, “cell lung cancer”, and “antibiotic use”, shifting the focus toward applying FMT to overcome therapy resistance and validate patient survival benefits. Consistent with the clustering temporal distribution, clusters #2 (“fecal microbiota transplantation”) and #6 (“anti pd 1 efficacy”) expanded rapidly and became the mainstream thematic hubs in this stage. Currently, the field is in a stage of mechanistic deepening and standardization [2025–2026], with emerging keywords like “dysbiosis”, “dietary fiber”, “chain fatty acids”, “tumor microenvironment”, “inflammation”, and “consensus statement”, highlighting the pursuit of molecular understanding, precision interventions, and the development of clinical guidelines to integrate this combinatorial strategy into routine practice. The latest emerging clusters #8 (“gastric cancer”), #10 (“hepatocellular carcinoma”) and #9 (“screening tests”) further verify the expansion of research to digestive malignancies and the rising demand for individualized treatment strategies. This evolution underscores a paradigm shift from initial descriptive correlations to mechanism-driven, precision immunotherapy.

Figure 9.

Keywords with the strongest citation bursts.

Discussion

General information

Over the past decade, substantial effort has been devoted to the application of FMT and ICIs in cancer immunotherapy. A seminal study published in Science in 2015 indicated that Bifidobacterium spp. enhanced anti-PD-L1 efficacy in mice, accelerating subsequent studies on FMT combined with ICIs (24). In this bibliometric analysis, we characterized trends and research hotspots in this field. The rapid rise in annual publications over this period, with a notable acceleration since 2019, reflects the growing clinical recognition of gut microbiota as a critical determinant of ICI efficacy. Microbiome studies and advances in research technologies have also propelled this field forward (29). Notably, over 60% of all papers were published in the last 3 years [2023–2025], signaling that this microbiota-ICI combinatorial strategy has rapidly transitioned from a niche hypothesis to a mainstream investigational priority within oncological immunotherapy.

At the country level, a striking decoupling exists between publication volume and network centrality. China, despite being the largest contributor globally, exhibits disproportionately low centrality, indicating that its research output stems mainly from domestically oriented, self-contained ecosystems rather than through globally integrated partnerships, a pattern corroborated by its high SCP ratio. In contrast, the United States, while ranking second in total publication volume, commands the highest centrality (0.53). It functions as the principal cross-regional bridge linking East Asian, European, and North American research clusters and acts as a core corridor for multinational projects. France and Canada, despite more modest output, display centrality values proportionally higher than several larger producers, suggesting their roles as regional connectors that bridge otherwise weakly linked segments of the network.

The institutional landscape mirrors the national productivity distribution, with the top 10 prolific institutions concentrated in China, the United States, France, and Canada (Table 2). The Chinese Academy of Medical Sciences and Fudan University exhibit the highest institutional centrality (0.23), yet this strong domestic connectivity does not translate into national-level international brokerage, as reflected by China’s low national centrality (0.03). The United States presents a contrasting pattern: its national centrality ranks highest (0.53), while its leading institutions show only moderate centrality (0.06). This reflects a distributed collaboration architecture, in which multiple institutions maintain independent international partnerships, collectively forming a dense cross-regional network. Despite these distinctive national strategies for building research networks, the collaboration landscape is anchored by three major institutional hubs, namely the University of Texas MD Anderson Cancer Center, Shanghai Jiao Tong University, and Université Paris-Saclay. Nevertheless, the limited cross-cluster cooperation among major institutions underscores the urgent need for strengthened global collaboration, unified data standards, and harmonized clinical protocols for FMT.

Leading researchers, including Routy, Bertrand, Wang, Yinghong, and Elkrief, Arielle, have formed highly productive collaborative groups that drive clinical and mechanistic progress. Journal distribution further illustrates the interdisciplinary nature of this field, with the majority of original studies published in specialty journals such as Frontiers in Immunology and Cancers, whereas landmark breakthroughs appear in high-impact journals such as Science and Nature Medicine. This pattern highlights the dependence of the field on synergistic progress in basic mechanistic research and clinical translation.

Research focus and hotspot

Bibliometric analysis enables the systematic identification of research hotspots and evolutionary trends in a specific field. Three distinct phases emerged from our keyword analysis: correlational observation [2015–2019], clinical validation [2020–2024], and mechanistic dissection [2025–2026]. This trajectory reflects a rational progression driven by the recognition that variable FMT outcomes demand deeper mechanistic understanding beyond taxonomic characterization. The current emphasis on microbial metabolites and TME reprogramming represents a critical shift toward functional interrogation, moving the field from descriptive taxonomy toward rigorous mechanistic elucidation and the establishment of standardized criteria for clinical translation.

Beyond melanoma and NSCLC, research has increasingly focused on digestive system malignancies, including CRC, GC, and HCC. The growing interest in digestive system tumors is underpinned by a strong biological rationale. The gut harbors the densest microbial communities in the human body and forms a specialized mucosal immune interface, rendering it an ideal platform to dissect microbiota-immune crosstalk. Among these, CRC has gained particular attention, as reflected by its high keyword centrality. CRC has attracted the most research interest for several reasons, including the close physical connection between CRC and gut microbes, widespread ICI refractoriness in microsatellite stable (MSS) CRC, easy acquisition of patient biospecimens, and mature preclinical CRC models for mechanistic validation (30). In GC, the application of FMT combined with ICIs is driven by the microbiota-immune crosstalk framework, the clinical challenge of limited ICI efficacy, and the promising results emerging from early preclinical studies. For HCC, the gut-liver axis represents a unique bidirectional communication network that links the intestinal microbiota and the liver, and cumulative evidence indicates that gut microbiota dysbiosis accelerates HCC progression through the gut-liver axis (31). Collectively, these findings underscore the expanding landscape of FMT-ICI research across digestive system tumors.

Keyword bursts further reflect an intensive focus on dysbiosis, dietary fiber, SCFAs, tumor microenvironment, and inflammation, signifying a concerted effort across the field to uncover molecular and metabolic mechanisms. TME, in particular, has attracted growing attention as a key mediator through which the microbiome exerts immunomodulatory effects. The strong emergence of “dietary fiber” and “SCFAs” suggests that dietary intervention may be a modifiable factor to improve FMT engraftment, an area that is currently under active investigation in clinical studies. The “screening tests” cluster reflects the increasing need for individualized donor selection, predictive biomarkers, and early identification of patients at risk for irAEs. Notably, the bursts of “consensus statement” and “international scientific association” indicate that the field has reached a critical juncture. Although the therapeutic potential of FMT combined with ICIs is increasingly recognized, standardized protocols for global clinical application are still lacking. Given the substantial geographic and ethnic variation in gut microbiota composition, a universal approach is unlikely to be feasible. Instead, a modular framework that allows for local adaptation while maintaining core quality criteria may offer a viable path forward.

Advances in the application of FMT combined with ICIs in digestive system malignancies

Historically, studies combining FMT with ICIs for cancer immunotherapy have predominantly focused on melanoma and NSCLC. Consistent with our bibliometric analysis, the research scope has expanded to encompass digestive system malignancies, including CRC, GC, and HCC.

FMT with ICIs in CRC

Among digestive system malignancies, CRC has received the most attention. ICIs have demonstrated remarkable efficacy in a subset of patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) CRC; however, their therapeutic benefits remain limited in the majority of patients with mismatch repair-proficient (pMMR) or MSS tumors (30). Emerging evidence suggests that FMT may partially reverse resistance to ICI monotherapy. In a single-arm, phase II trial, FMT combined with tislelizumab (anti-PD-1) and fruquintinib was evaluated in patients with refractory MSS metastatic colorectal cancer (mCRC). The combination achieved an ORR of 20% (95% CI: 5.7–43.7) and a disease control rate (DCR) of 95% (95% CI: 75.1–99.9), with a median progression-free survival (PFS) of 9.6 months (95% CI: 4.1–15.1), suggesting promising clinical potential for this triple regimen (30). Mechanistic studies have also elucidated the effects of FMT. High intratumoral Fusobacterium nucleatum (Fn) levels correlated with better anti-PD-1 responses. FMT from patients with high-Fn MSS CRC sensitized germ-free mice to anti-PD-1, with Fn-derived butyrate inhibiting histone deacetylase (HDAC) 3/8 in CD8⁺ T cells, leading to PD-1 downregulation, thereby reversing T-cell exhaustion (32). Notably, Fn is abundant in CRC and is positively correlated with tumor progression (33). However, a study involving 1,041 patients with CRC revealed that Fn levels were negatively correlated with TILs in MSI CRC, but positively associated with TILs in MSS CRC (34). These findings suggest that Fn exerts differential effects on the TME based on the microsatellite status of CRC. FMT has also been reported to increase the abundance of butyrate-producing bacteria, such as Roseburia intestinalis, which activate the butyrate/olfactory receptor family 51 (OR51E1)/RALB pathway, and promote autophagy and tumor cell death (35). In addition to its therapeutic efficacy, FMT may alleviate irAEs. In a study of ICI-associated immune-mediated colitis, FMT as a salvage therapy led to symptom improvement in 83% of patients and clinical remission in 92%, correlating with the restoration of α-diversity and engraftment of specific beneficial bacterial taxa (36). However, the current evidence supporting FMT for refractory MSS CRC is primarily derived from single-arm trials, small studies, and preclinical models (37). Large-scale, multicenter randomized controlled trials (RCTs) are needed to validate the efficacy, safety, and optimization potential of the treatment protocols.

FMT with ICIs in GC

In contrast to CRC, studies specifically evaluating FMT in GC are relatively limited. Although preliminary evidence suggests a potential therapeutic benefit, definitive conclusions have not yet been reached. A clinical trial evaluated the combination of FMT derived from donors who responded to ICIs with anti-PD-1 therapy in patients with metastatic GC, esophageal squamous cell carcinoma, and HCC (19). This study reported sustained remodeling of gut microbiota and its clinical benefits in a subset of patients. Although this trial did not report the outcomes for the GC subgroups separately, the collective findings provide a rationale for further investigation of FMT to overcome ICI resistance in GC. An open-label, single-arm, single-center, phase I trial evaluated the safety and preliminary efficacy of the combined treatments of FMT from healthy donors with anti-PD-1 therapy in patients with advanced gastrointestinal cancers refractory to PD-1/PD-L1 inhibition (38). The study enrolled ten patients, including eight with GC and two with CRC. The combination regimen demonstrated a favorable safety profile with no severe adverse events reported. Preliminary efficacy signals were observed with an ORR of 20% (2/10) and a DCR of 40% (4/10). When the analysis was confined to patients with GC, ORR and DCR increased to 25% (2/8) and 50% (4/8), respectively. The clinical benefits were correlated with the engraftment of donor-derived immunogenic microbes and an activated peripheral immune phenotype. This phase I study established the feasibility and safety of FMT combined with anti-PD-1 therapy in refractory GC, although the efficacy signals require confirmation in larger trials. High-quality clinical data, specifically for GC, remain limited, underscoring the need for more prospective multicenter trials to further clarify efficacy and safety, and to optimize treatment regimens.

FMT with ICIs in HCC

The gut microbiome profoundly modulates both hepatic and systemic immune responses via the gut-liver axis, thereby influencing initiation, progression, and response to immunotherapy in HCC (39). Kim et al. extended the utility of FMT beyond melanoma to other solid tumors, including HCC, suggesting its potential to reverse ICI resistance in HCC (19). In addition, research has indicated that gut dysbiosis, particularly the reduction in beneficial bacteria, such as Anaerotruncus colihominis and Dysosmobacter welbionis, is associated with an increased risk of intrahepatic metastasis in HCC (40). Dysbiosis promotes metastasis by stimulating neutrophil inflammation and excessive neutrophil extracellular trap (NET) formation, which drives tumor angiogenesis. FMT from healthy donors reverses this imbalance, restores beneficial bacteria, and inhibits NET-driven metastasis, highlighting its therapeutic potential (40). Although studies on the use of FMT in HCC immunotherapy remain limited, ongoing phase II clinical trials are required to evaluate its potential. Two key investigations (FLORA and FAB-HCC) are examining FMT combined with atezolizumab (anti-PD-L1) and bevacizumab in patients with advanced HCC refractory to prior immunotherapy (41,42). Both trials share core objectives: evaluating treatment safety, radiographic response rates, survival outcomes, and exploring correlative changes in gut microbiota and immune activity following FMT. Although specific results from these trials have not yet been reported, these ongoing studies represent important advancements in precision oncology. These findings may offer new strategies to enhance the efficacy of immunotherapy and overcome resistance in patients with HCC, thereby facilitating the development of microbiota‑based therapies.

In summary, malignancies of the digestive system represent a particularly promising area for the combination of FMT and ICIs. In CRC, preliminary evidence suggests that FMT may reverse ICI resistance in MSS/pMMR tumors, the largest patient subgroup with inherently poor ICI responsiveness. Clinical translation, however, is limited by substantial interindividual gut microbiota heterogeneity, non-standardized FMT donor screening criteria, and a lack of strain-specific targeted precision intervention regimens. Early-phase clinical trials in GC have demonstrated the safety and preliminary efficacy of this approach, laying a foundation for further exploration in ICI-refractory cases. These trials also face several challenges, including insufficient sample sizes, highly heterogeneous TME driven by Helicobacter pylori infection, gastric acidity, and variable nutrient availability, as well as poorly defined microbe-mediated immune signaling pathways (43). In HCC, the gut-liver axis provides a compelling biological rationale for FMT to modulate hepatic immunity and potentially inhibit metastasis. Nevertheless, clinical translation is complicated by the confounding effects of underlying chronic liver disease, including cirrhosis, portal hypertension, and bile acid dysregulation, on gut microbial composition, and safety concerns related to FMT administration in patients with compromised hepatic function. Thus, most available evidence is still derived from preclinical models, with mature clinical data lacking (44). Collectively, these findings establish FMT as a compelling proof-of-concept in digestive system malignancies, yet its broad clinical implementation remains contingent upon overcoming tumor- and disease-specific translational barriers through rigorously designed, disease-stratified trials.

Distribution of evidence levels

Beyond tracking thematic shifts, assessing the distribution of evidence levels over time provides a complementary perspective on translational progress in this field. Lin et al. identified only 10 clinical studies in their meta-analysis of FMT combined with ICIs for cancer treatment, 3 of which were two-arm trials, and the remaining 7 were single-arm studies (18). In a systematic review of FMT across various cancer therapies, Wekking et al. further confirmed the lack of large-scale RCT efficacy data, even within the immunotherapy subgroup (37). The evidence for FMT combined with ICIs is derived predominantly from early-phase, single-arm studies. A pivotal step toward higher-level evidence came in 2026 with the first RCT in this field, the phase 2 TACITO trial in metastatic renal cell carcinoma, which demonstrated a clinically meaningful improvement in 12-month PFS with donor FMT vs. placebo (70% vs. 41%), approaching statistical significance (P=0.053) (45). While this trial did not formally meet its primary endpoint, it provides a strong rationale for adequately powered phase 3 trials, which are now critically needed to define the clinical role of FMT-ICI combination therapy.

Mechanisms by which FMT modulates ICI efficacy

The mechanisms by which FMT improves ICI response are complex. Our keyword burst analysis pointed to several current priorities, including gut dysbiosis, SCFAs, and the TME. The following sections explore how these factors mediate the effects of FMT on ICI outcomes.

Remodeling of gut microbiota

Alterations in the diversity and composition of the gut microbiota underlie variations in the efficacy of ICI treatment following FMT. High α-diversity of the gut microbiota is associated with favorable responses to ICI therapy, possibly by facilitating CD8⁺ T-cell infiltration into tumors (46,47). ICI therapy itself can also induce dysbiosis, characterized by reduced microbial diversity and a shift toward a Gram-negative dominant enterotype (48). FMT can reverse this dysbiosis by introducing a healthy microbial community and reshaping the microbial composition (49), and these changes affect subsequent ICI efficacy. Enrichment of beneficial bacteria, such as Akkermansia muciniphila, Bifidobacterium, Ruminococcus, and Faecalibacterium, has been consistently associated with enhanced anti-PD-1 responses (50,51). These microbes may promote T-cell activation, enhance antitumor immune responses, and maintain gut homeostasis (52). Among these, Akkermansia muciniphila has attracted particular attention, as it enhances dendritic cell maturation and interleukin-12 (IL-12) secretion, promoting the recruitment of CD4⁺ T cells and the subsequent activation of CD8⁺ T cells within the TME (10), and it also strengthens intestinal barrier integrity and reduces systemic inflammation (53). Conversely, the loss of detrimental bacterial taxa, including Enterocloster, Clostridium, Streptococcus, and Dialister, after FMT is equally critical, as these species have been linked to immunosuppressive or pro-inflammatory conditions (54). Thus, the therapeutic effects of FMT may be driven not only by the enrichment of beneficial microbes but also, and perhaps more importantly, by the elimination of detrimental microbial communities.

A recent meta-analysis that reprocessed stool metagenomic sequencing data from 15 melanoma cohorts further refined this framework, where trials combining FMT with ICIs exhibited distinct microbial communities and metabolic shifts, including amino-acid, nucleotide, and cofactor metabolism, compared to ICI monotherapy (55). Microbiome signatures of response are treatment-context dependent, and no single universal species predicted response across all studies, suggesting that future research should prioritize functional guilds and community-level networks over individual taxa.

Modulation of gut microbial metabolites

FMT modulates ICI efficacy by altering the metabolic profile of the gut microbiome. SCFAs, primarily butyrate, acetate, and propionate, are generated from dietary fiber fermentation and serve as critical regulators of host immunity. Dietary fiber intake thus represents a modifiable factor that could shape the SCFA-producing capacity of the engrafted microbiota. Consistent with our bibliometric analysis, SCFAs and dietary fiber have emerged as key research hotspots in the combination of FMT and ICI therapy. In preclinical studies, FMT markedly elevates the levels of butyrate, acetate, and caproic acid (56,57). For instance, the gut microbiota of NSCLC responders to chemo-immunotherapy exhibits higher SCFA production potential at the metabolic pathway level. FMT from such donors into animal models enhances therapy response and intratumoral effector T cell activity (58). SCFAs regulate tumor progression through immune cell activation, epigenetic modifications, and inflammatory responses (59). Butyrate enhances the efficacy of anti-PD-1 therapy by upregulating the transcription of Pdcd1 (encoding PD-1) and Cd28 by increasing histone 3 lysine 27 acetylation (H3K27ac) at their promoter regions and promoting antitumor cytokine production via the modulation of T-cell receptor signaling pathways (60). Bachem et al. determined that butyrate induces a forkhead box O (FOXO)-driven stemness program in CD8⁺ T cells, enhancing the response of melanoma cells to ICIs (61). Besides T cells, butyrate boosts natural killer (NK) cell cytotoxicity and maturation, activates macrophages to strengthen the intestinal mucus barrier, and suppresses dendritic cell antigen presentation, thereby reducing pro-inflammatory cytokines (62).

However, SCFAs can also exert context-dependent immunosuppressive effects. In murine melanoma models and patients with metastatic melanoma, higher blood butyrate and propionate levels correlated with resistance to CTLA-4 blockade and increased regulatory T cells (Treg) frequency (63). Zhao et al. reported that acetate accumulation in lung adenocarcinoma tumors activated free fatty acid receptor 2 (FFAR2) on myeloid-derived suppressor cells (MDSCs), enhancing their immunosuppressive function (64). In contrast, genetic ablation of FFAR2 or pharmacologic inhibition of FFAR2 reduced MDSCs in the TME, increased CD8⁺ T-cell infiltration and activity, and restored sensitivity to anti-PD-1therapy. The divergent roles of SCFAs in tumor regulation may be based on microbiota composition, tumor heterogeneity, and host metabolic context (59). These opposing observations suggest that the net impact of FMT on ICI efficacy depends on the functional metabolite profile, including total SCFA concentration, individual SCFA abundance, their tissue distribution, and the host immune landscape.

Such complexity argues against a “one-donor-fits-all” strategy and supports metabolome-guided donor selection, in which donor stool is screened for a functional metabolic signature matched to the recipient’s tumor type and baseline microbiota. Adjunctive dietary interventions, such as controlled fiber supplementation, can be designed to standardize or optimize the metabolic output of FMT, thereby enhancing its synergistic effect with ICI therapy.

Modification of the TME

FMT enhances the antitumor activity of ICIs through multiple mechanisms that converge on the TME. First, FMT reshapes immune cell composition within the TME. Accumulating evidence indicates that after FMT, the TME consistently shows markedly increased infiltration of CD8⁺ T, Th1, and antigen-presenting cells in responders (20). CD8⁺ T cells serve as the principal effectors of antitumor immunity, correlating with improved tumor cell clearance (65). Th1 cells further support antitumor responses through secretion of interferon-gamma (IFN-γ), which activates macrophages and NK cells. Increased antigen-presenting cell abundance promotes T cell priming and expansion. Conversely, FMT has been shown to reduce immunosuppressive cell populations, including MDSCs and Treg cells, within the TME (11,20,66). The depletion of these populations alleviates suppression of effector T-cell function and facilitates antitumor immunity.

In addition, FMT augments immune cell function. It activates mucosal-associated invariant T (MAIT) cells, characterized by decreased PD-1 expression and increased CD69 expression (67), consistent with improved immune surveillance capacity. FMT promotes dendritic cell maturation and antigen-presenting function, thereby strengthening downstream T-cell responses (68). NK cell cytotoxicity is enhanced after FMT, contributing to innate antitumor defense (69). FMT also promotes macrophage polarization toward an M1 phenotype, which is associated with proinflammatory and antitumor activity. Moreover, FMT has the potential to regulate cytokine and chemokine production (49). Increased systemic levels of IFN-γ and IL-2 have been reported following FMT, both of which play central roles in antitumor immunity (70). Chemokines, including CXCL9 and CXCL10, are upregulated, promoting T-cell infiltration into the TME (71).

These coordinated effects facilitate the conversion of immunologically “cold” tumors into “hot” T cell-inflamed tumors that are more responsive to ICIs. However, this benefit is not universal. In some non-responders, FMT has been associated with the persistence or expansion of Tregs and MDSCs, limited lymphocyte infiltration, and impaired antigen presentation, all of which contribute to suboptimal clinical outcomes (72). These observations highlight the need to better understand how FMT modulates the TME to optimize patient selection and therapeutic efficacy. In parallel, the intratumoral microbiota (ITM) has recently gained attention for its role in remodeling the TME. ITM can directly affect genomic stability, metabolism, signaling pathways, and cellular plasticity of tumor cells, while indirectly shaping tumor evolution via its effects on immune and stromal components in the TME (73). However, evidence that FMT directly alters the ITM composition or function is limited. Investigating the crosstalk between FMT and the ITM may therefore represent a promising frontier for optimizing ICI responses.

Collectively, the preceding sections have separately discussed the regulatory effects of FMT on gut microbiota remodeling, metabolite-mediated immune regulation, and TME reprogramming. However, these three components are not independent but rather closely intertwined. Microbiota remodeling enriches gut microbial metabolites, particularly SCFAs, which shape the TME and modulate ICI responses via immune cell metabolic reprogramming (28). A deeper mechanistic understanding of this triad is essential to advancing the clinical translation of FMT combined with ICIs.

Clinical application of FMT combined with ICIs: Challenges and future directions

FMT combined with ICIs has the potential to enhance antitumor efficacy in multiple solid tumors; however, its clinical application still faces several challenges. The “screening tests” cluster primarily encompasses donor-recipient selection, predictive biomarkers for ICI response, and early prediction of irAEs. Donor selection remains a major challenge because standardized criteria have not been established. Current evidence suggests that the composition of donor gut microbiota influences the efficacy of FMT. Donors enriched in immunogenic taxa, such as Akkermansia and Muribaculaceae, but lacking potentially pathogenic species, such as Enterocloster citroniae and Clostridium innocuum, are more likely to trigger clinical responses (17,74). Two main donor sources are currently being investigated: patients who exhibit durable responses to ICIs, and healthy volunteers. Feces derived from patients inherently carry a higher risk of infection and require strict screening protocols. Considering the challenges associated with recruiting patient-derived donors, healthy volunteers have emerged as a more favorable option to ensure long-term and stable access to fecal sources (16). Future studies are urgently needed to define the “core functional microbiota” required by recipients, and to standardize a set of screening criteria. Potential solutions include establishing a multidimensional donor evaluation system based on metagenomic, metabolomic, and immunological profiling combined with artificial intelligence to predict donor-recipient matching (20).

Furthermore, the enrollment and management of recipients remain unstandardized. The baseline characteristics of recipients substantially affect the efficacy of FMT combined with ICIs. Additional factors potentially associated with improved responsiveness to the combination approach include the absence of liver metastases (75), a high tumor mutational burden (TMB ≥9) (76), alterations in genes involved in epigenetic regulation (77), and positivity for certain cancer tissue signature markers (78). Nevertheless, these candidate biomarkers have yet to be incorporated into a clinically applicable framework for recipient selection. Reliable predictive biomarkers for patient stratification, such as microbial signatures, metabolomic profiles, and systemic immune phenotypes, represent a major research priority moving forward.

Another challenge is the lack of standardized protocols for engraftment procedures and colonization assessments following FMT. Several unresolved issues remain in this area, including the route of administration, treatment frequency, timing relative to immunotherapy, and monitoring of microbial engraftment (79). Currently, colonization evaluation relies primarily on metagenomic sequencing of paired donor‑recipient stool samples or the assessment of humoral immune responses against donorderived bacteria (26). Future studies should identify the key determinants of successful engraftment and establish optimal sampling time points that reflect functional colonization.

Procedural safety evaluations should be integrated into future FMT trial designs. In a multicenter phase 2 clinical trial, 13 patients (65%) in the melanoma cohort receiving dual immunotherapy (nivolumab plus ipilimumab) experienced grade 3 or higher irAEs, which were substantially associated with donor microbiota composition enriched in Prevotella spp (17). This finding underscores the urgent need to identify risk factors for early prediction of irAEs, with donor microbiota composition representing a promising predictive marker. Long-term follow-up studies are necessary to enable systematic collection and analysis of clinical data, microbiome changes, and potential adverse events. Particular emphasis should be placed on elucidating the effect of FMT on irAEs, including its potential to exacerbate or ameliorate adverse events.

To address the current limitations of FMT, Jiading et al. proposed a “4D” framework, including diversity, diffusion, depth, and delicacy, to fully harness the therapeutic potential of microbial manipulation (79). Diversity covers a broad range of microbial species across anatomical sites, such as fecal and intratumoral microbiomes, and may vary between primary and metastatic sites. Diffusion focuses on the standardization of donor-dependent FMT and the balance between ICI efficacy and toxicity. Depth emphasizes the exploration of subspecies and natural chassis strains, and the differences between primary and metastatic tumors. Finally, delicacy highlights the application of personalized regimens, engineered bacteria, and metabolite modulation in future immunotherapy. Our bibliometric analysis also revealed strong bursts of “consensus statement” and “international scientific association”, highlighting the urgent need for unified clinical guidelines, standardized protocols, and interdisciplinary cooperation to advance the safe and effective clinical translation of FMT combined with ICIs.

Beyond conventional FMT, innovative strategies are emerging to overcome the existing limitations and advance precision microbiota-based immunotherapy. Autologous strain therapy is an emerging approach that uses native commensal bacteria isolated from a patient, modified to express immunomodulators and reintroduced into the same individual (80). These strains enable stable, long-term colonization and sustained expression of therapeutic genes to regulate host homeostasis and prevent immune rejection. Nanocarriers modified with microbiota-targeting adhesion molecules can guide commensals to tumors with specific surface signatures (81). When integrated with GlycoCaging, future systems may allow TME-specific drug release via activation by microbial metabolic enzymes, thus preserving the structure and function of native gut microbiota (82). In addition, artificial intelligence and multi-omics integration facilitate personalized prediction of treatment responses, enabling the early identification of potential beneficiaries and non-responders before treatment. Collectively, these approaches hold great promises for optimizing the efficacy of FMT, standardizing clinical practice, and accelerating the clinical translation of safer and more precise microbiota-based interventions in combination with ICIs.

Limitations

Our findings, while comprehensive, are subject to certain methodological and contextual limitations. First, limiting the literature search to the Web of Science Core Collection may have led to the omission of relevant studies indexed in other databases, and the search results may also vary depending on the specific databases accessible to different institutions. Both factors could potentially bias the overall analysis of the global research landscape. Second, restricting inclusion to English-language articles may have overlooked non-English language studies that have made important contributions to this field. Future research should incorporate multiple databases and expand language coverage to address these limitations. Third, the dynamic nature of this rapidly evolving field means that new high-impact publications appearing after the search date (March 11, 2026) are not captured. Therefore, our findings should be interpreted as a snapshot of the research landscape up to that date. Finally, the use of different software versions or analytical approaches may introduce minor inconsistencies in the results.

Conclusions

This bibliometric analysis outlines the global research landscape of FMT combined with ICIs in cancer therapy, revealing a field that has expanded rapidly since 2019, with China and the United States as the leading contributors. The thematic evolution follows a three-stage trajectory: correlational observation, clinical translation, and mechanistic dissection, while the evidence base is now transitioning toward more rigorous clinical validation. The field has expanded from melanoma and NSCLC to digestive malignancies, with emerging hotspots including dysbiosis, SCFAs, TME, and standardized clinical protocols. To address these gaps, we propose several prioritized research directions. First, large-scale RCTs are urgently needed to validate efficacy across different tumor types including CRC, GC, and HCC. Second, standardized protocols for donor-recipient screening, FMT administration, and engraftment assessment must be established through comparative trials to reduce inter-trial heterogeneity. Third, multi-omics integration and artificial intelligence assisted approaches should be leveraged to identify predictive biomarkers and enable precision microbiome interventions. Fourth, mechanistic studies should focus on the functional roles of microbial metabolites and their context-dependent effects in TME modulation. Finally, systematic surveillance of irAEs and exploration of next-generation microbiome technologies will be essential to translate these strategies into clinical practice. Strengthening international collaboration and harmonizing clinical protocols across borders will be essential to accelerate progress and ensure the global application of this combinatorial strategy.

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