The integration of fecal microbiota transplantation (FMT) with immune checkpoint inhibitors (ICIs) presents a promising approach for enhancing cancer treatment efficacy and overcoming therapeutic resistance. This review critically examines the controversial effects of FMT on ICIs outcomes and elucidates the underlying mechanisms. We investigate how FMT modulates gut microbiota composition, microbial metabolite profiles, and the tumor microenvironment, thereby influencing ICIs effectiveness. Key factors influencing FMT efficacy, including donor selection criteria, recipient characteristics, and administration protocols, are comprehensively discussed. The review delineates strategies for optimizing FMT formulations and systematically monitoring post-transplant microbiome dynamics. Through a comprehensive synthesis of evidence from clinical trials and preclinical studies, we elucidate the potential benefits and challenges of combining FMT with ICIs across diverse cancer types. While some studies report improved outcomes, others indicate no benefit or potential adverse effects, emphasizing the complexity of host-microbiome interactions in cancer immunotherapy. We outline critical research directions, encompassing the need for large-scale, multi-center randomized controlled trials, in-depth microbial ecology studies, and the integration of multi-omics approaches with artificial intelligence. Regulatory and ethical challenges are critically addressed, underscoring the imperative for standardized protocols and rigorous long-term safety assessments. This comprehensive review seeks to guide future research endeavors and clinical applications of FMT-ICIs combination therapy, with the potential to improve cancer patient outcomes while ensuring both safety and efficacy. As this rapidly evolving field advances, maintaining a judicious balance between openness to innovation and cautious scrutiny is crucial for realizing the full potential of microbiome modulation in cancer immunotherapy.

Immune checkpoint blockade therapies have markedly advanced cancer treatment by invigorating antitumor immunity and extending patient survival. However, therapeutic resistance and immune-related toxicities remain major concerns. Emerging evidence indicates that microbial dysbiosis diminishes therapeutic response rates, while a diverse gut ecology and key beneficial taxa correlate with improved treatment outcomes. Therefore, there is a growing understanding that manipulating the gut microbiota could boost therapy efficacy. This review examines burgeoning methods that target the gut microbiome to optimize therapy and innovative diagnostic tools to detect dysbiosis, and highlights challenges that remain to be addressed in the field.

The gut microbiota has emerged as a critical determinant of immune checkpoint inhibitor (ICI) efficacy, resistance, and toxicity. Retrospective and prospective studies profiling the taxonomic composition of intestinal microbes of patients treated with ICI have revealed specific gut microbial signatures associated with response. By contrast, dysbiosis, which can be caused by chronic inflammatory processes (such as cancer) or comedications, is a risk factor of resistance to ICI. Recent large-scale meta-analyses have confirmed that antibiotic (ATB) use before or during ICI therapy alters the microbiota repertoire and significantly shortens overall survival, even after adjusting for prognostic factors. These results underscore the importance of implementing ATB stewardship recommendations in routine oncology practice. Microbiota-centered interventions are now being explored to treat gut dysbiosis and optimize ICI responses. Early-phase clinical trials evaluating fecal microbiota transplantation (FMT) from ICI responders or healthy donors have shown that this approach is safe and provided preliminary data on potential efficacy to overcome both primary and secondary resistance to ICI in melanoma, non-small cell lung cancer, and renal cell carcinoma. More targeted interventions including live bacterial products including Clostridium butyricum and Akkermansia massiliensis represent novel microbiome-based adjunct therapies. Likewise, dietary interventions, such as high-fiber diets, have shown promise in enhancing ICI activity. In this ASCO Educational Book, we summarize the current state-of-the-evidence of the clinical relevance of the intestinal microbiota in cancer immunotherapy and provide a practical guide for ATB stewardship.

Bacteria are associated with certain cancers and may induce genetic instability and cancer progression. The gut microbiome modulates the response to cancer therapy. Training machine learning models with response associated taxa or bacterial genes predict patients' response to immunotherapies with moderate accuracy. Clinical trials targeting the gut microbiome to improve immunotherapy efficacy have been conducted. While single bacterial strains or small consortia have not be reported yet to be successful, encouraging results have been reported in small single arm and randomized studies using transplant of fecal microbiome from cancer patients who successfully responded to therapy or from healthy volunteers.

Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality worldwide, highlighting the urgent need for novel preventive and therapeutic strategies. Emerging research highlights the crucial role of the gut microbiota, including bacteria, fungi, viruses, and their metabolites, in the pathogenesis of CRC. Dysbiosis, characterized by an imbalance in microbial composition, contributes to tumorigenesis through immune modulation, metabolic reprogramming, and genotoxicity. Specific bacterial species, such as Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis, along with fungal agents like Candida species, have been implicated in CRC progression. Moreover, viral factors, including Epstein-Barr virus and human cytomegalovirus, are increasingly recognized for their roles in promoting inflammation and immune evasion. This review synthesizes the latest evidence on host-microbiome interactions in CRC, emphasizing microbial metabolites, such as short-chain fatty acids and bile acids, which may act as both risk factors and therapeutic agents. We further discuss the latest advances in microbiota-targeted clinical applications, including biomarker-assisted diagnosis, next-generation probiotics, and microbiome-based interventions. A deeper understanding of the role of gut microbiome in CRC pathogenesis could pave the way for diagnostic, preventive, and personalized therapeutic strategies.

The composition of the microbiota in patients has been shown to correlate with cancer progression and response to therapy, highlighting unique opportunities to improve patient outcomes. In this review, we discuss the challenges and advancements in understanding the chemical mechanisms of specific microbiota species, pathways, and molecules involved in cancer progression and treatment. We also describe the modulation of cancer and immunotherapy by the microbiota, along with approaches for investigating microbiota enzymes and metabolites. Elucidating these specific microbiota mechanisms and molecules should offer new opportunities for developing enhanced diagnostics and therapeutics to improve outcomes for cancer patients. Nonetheless, many microbiota mechanisms remain to be determined and require innovative chemical genetic approaches.

Immune checkpoint inhibitors (ICIs) constitute a major breakthrough in the field of cancer therapy; their use has resulted in improved outcomes across various tumour types. However, ICIs can cause a diverse range of immune-related adverse events (irAEs) that present a considerable challenge to the efficacy and safety of these treatments. The gut microbiota has been demonstrated to have a crucial role in modulating the tumour immune microenvironment and thus influences the effectiveness of ICIs. Accumulating evidence indicates that alterations in the composition and function of the gut microbiota are also associated with an increased risk of irAEs, particularly ICI-induced colitis. Indeed, these changes in the gut microbiota can contribute to the pathogenesis of irAEs. In this Review, we first summarize the current clinical challenges posed by irAEs. We then focus on reported correlations between alterations in the gut microbiota and irAEs, especially ICI-induced colitis, and postulate mechanisms by which these microbial changes influence the occurrence of irAEs. Finally, we highlight the potential value of gut microbial changes as biomarkers for predicting irAEs and discuss gut microbial interventions that might serve as new strategies for the management of irAEs, including faecal microbiota transplantation, probiotic, prebiotic and/or postbiotic supplements, and dietary modulations.

This study aims to comprehensively evaluate the hematologic toxicity profiles, toxicity spectrum, and safety rankings of immune checkpoint inhibitors (ICIs) used for digestive system tumors. The PubMed, Cochrane Library, Web of Science, and Embase databases were systematically searched from inception to August 2024 to identify randomized controlled trials (RCTs). The primary outcome was anemia, while secondary outcomes included neutropenia, neutrophil count decreased, thrombocytopenia, platelet count decreased, leukopenia, white blood cell (WBC) count decreased, lymphocyte count decreased, and febrile neutropenia (FN). Subgroup analyses were performed based on tumor type, country category, study phase, ICI regimen, control group, chemotherapy regimen, ICI plus different chemotherapy regimens. Two reviewers independently selected the studies, extracted data according to pre-specified criteria, and assessed the risk of bias using the Cochrane Collaboration risk of bias tool. RevMan 5.4 software was utilized to visualize the risk of bias assessments. Stata 16.0 was used to conduct network meta-analysis, sensitivity analysis and meta-regression. 25 phase II and III RCTs (n = 15216) were included. The general safety of ICIs ranked from high to low for grade 1-5 anemia were as follows: avelumab, nivolumab, pembrolizumab, sintilimab, camrelizumab, and tislelizumab. For grade 3-5 anemia, the general safety profile of the ICIs were as follows, from highest to lowest: avelumab, nivolumab, pembrolizumab, sintilimab, and camrelizumab. Compared to chemotherapy, treatment-related hematologic toxicities with ICIs occurred primarily in grade 1-5 anemia, neutropenia, thrombocytopenia, leukopenia, and WBC count decreased. Taking ICI monotherapy, nivolumab plus ipilimumab were generally safer than taking chemotherapy, one ICI drug with chemotherapy, or two ICI drugs with chemotherapy. In terms of grade 1-5 hematologic toxicities, tislelizumab had the highest risk of neutropenia and leukopenia; the primary treatment-adverse events (AEs) for sintilimab was neutrophil count decreased and WBC count decreased; the primary treatment-related AE associated with nivolumab was platelet count decreased; camrelizumab posed the highest risk for lymphocyte count decreased. In terms of grade 3-5 hematologic toxicities, pembrolizumab was predominantly linked to neutropenia; sintilimab showed the greatest risk for neutrophil count decreased, platelet count decreased, and lymphocyte count decreased; avelumab was most associated with WBC count decreased. FN primarily manifested as grade 3-5, with camrelizumab having the highest risk. Among agents used in gastric or gastroesophageal junction cancer, avelumab demonstrated the most favorable safety profile for anemia. Each treatment regimen has its unique safety profile. Early identification and management of ICI-related hematologic toxicities are essential in clinical practice.Systematic Review Registration: PROSPERO CRD42024571508.

In the phase II NIMBUS trial, patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) and high tumor mutational burden (TMB ≥ 9 mut/Mb) received nivolumab (3 mg/kg biweekly) and low-dose ipilimumab (1 mg/kg every 6 weeks) for 2 years or until progression. The primary endpoint was objective response rate (ORR) per RECIST 1.1 criteria. Among 30 patients enrolled, the median TMB was 10.9 mut/Mb (range: 9-110) and the confirmed objective response rate was 20%. Secondary endpoints included progression-free survival, overall survival, clinical benefit rate, and safety and tolerability, including immune-related adverse events (irAEs). A prespecified correlative outcome was to evaluate the ORR in patients with a TMB ≥ 14 mut/Mb. Patients with TMB ≥ 14 mut/Mb (n = 6) experienced higher response rates (60% vs 12%; p = 0.041) and showed a trend towards improved progression-free survival and overall survival compared to patients with TMB < 14 mut/Mb. Exploratory genomic analyses suggested that ESR1 and PTEN mutations may be associated with poor response, while clinical benefit was associated with a decrease or no change in tumor fraction by serial circulating tumor DNA during treatment. Stool microbiome analysis revealed that baseline blood TMB, PD-L1 positivity, and immune-related diarrhea are associated with distinct taxonomic profiles. In summary, some patients with hypermutated HER2-negative MBC experience extended clinical benefit with a dual immunotherapy regimen; a higher TMB, and additional genomic and microbiome biomarkers may optimize patient selection for therapy with nivolumab plus low-dose ipilimumab. (Funded by Bristol Myers Squibb; ClinicalTrials.gov identifier, NCT03789110).

Cancer has long been associated with genetic and environmental factors, but recent studies reveal the important role of gut microbiota in its initiation and progression. Around 13% of cancers are linked to infectious agents, highlighting the need to identify the specific microorganisms involved. Gut microbiota can either promote or inhibit cancer growth by influencing oncogenic signaling pathways and altering immune responses. Dysbiosis can lead to cancer, while certain probiotics and their metabolites may help reestablish micro-ecological balance and improve anti-tumor immune responses. Research into targeted approaches that enhance therapy with probiotics is promising. However, the effects of probiotics in humans are complex and not yet fully understood. Additionally, methods to counteract harmful bacteria are still in development. Early clinical trials also indicate that modifying gut microbiota may help manage side effects of cancer treatments. Ongoing research is crucial to understand better how gut microbiota can be used to improve cancer prevention and treatment outcomes.

Systemic adjuvant therapy is indicated in patients with high-risk, resected melanoma to reduce recurrence risk and potentially improve survival rates. Monoclonal antibodies (mAbs) target immune checkpoints and have made significant advances as systemic adjuvant therapies.

This review discusses the main clinical trials that tested adjuvant mAbs in resected high-risk melanoma, including anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1); in addition to newer immunotherapies being tested in the adjuvant setting, including anti-lymphocyte activation gene 3 (LAG-3). We also briefly discuss targeted therapies as an alternative choice. Moreover, we highlight the pros and cons of using mAbs in the adjuvant setting, the reported adverse events (AEs), and the quality of life impact. Finally, we report data related to biomarker studies tested in the context of these clinical trials.

Immune checkpoint inhibitors (ICIs) have been shown to significantly improve relapse-free survival (RFS) as adjuvant therapy for high-risk melanoma. The long-term impact on overall survival (OS) was demonstrated in two trials that tested ipilimumab as compared to placebo (EORTC18071) and interferon-α (ECOG-ACRIN E1609). Furthermore, emerging data with neoadjuvant therapy followed by surgery and adjuvant therapy utilizing ICIs have demonstrated improved outcomes in the management of locoregionally advanced disease when compared to upfront surgery followed by adjuvant therapy alone.

The development of nucleic acid and protein drugs for oral delivery has lagged behind their production for conventional nonoral routes. Over the past decade, the evolution of DNA- and RNA-based technologies combined with the innovation of state-of-the-art delivery vehicles for nucleic acids has brought rapid advancements to the biopharmaceutical field. Nucleic acid therapies have the potential to achieve long-lasting effects, or even cures, by inhibiting or editing genes, which is not possible with conventional small-molecule drugs. However, challenges and limitations must be addressed before these therapies can provide cures for chronic conditions and rare diseases, rather than only offering temporary relief. Nucleic acids and proteins face premature degradation in the acidic, enzyme-rich stomach environment and are rapidly cleared by the liver. To overcome these challenges, various delivery vehicles have been developed to transport therapeutic compounds to the intestines, where the active compounds are released and gut microbiota and mucosal immune system also play an important role. This review provides a comprehensive overview of the promises and pitfalls associated with the oral route of administration of biologics, current delivery systems, applications of orally delivered therapeutics, and the challenges and considerations for translation of nucleic acid and protein therapeutics into clinical practice.

This review discusses the epidemiology, pathophysiology, and factors associated with refractory immune-mediated diarrhea and colitis (r-IMDC), emphasizing tailored treatment strategies.

The current literature on r-IMDC was reviewed using PubMed (2015-2025), focusing on clinical trials, meta-analyses, and case reports relevant to its management.

Effectively managing r-IMDC is crucial for balancing toxicities and antitumor response. Available second and third-line management options for r-IMDC cases must be carefully evaluated. Future perspectives include development of standardized protocols beyond second-line therapies and predictive biomarkers to enable personalized treatment.

The microbiome is essential for maintaining human health and is also a key factor in the development and progression of various diseases, including cancer. Growing evidence has highlighted the microbiome's significant impact on cancer development, progression, and treatment outcomes. As research continues to unfold, the microbiome and its modulation stand out as a promising frontier in cancer research and therapy. This review highlights current literature on the interplay between various cancer treatment modalities and human microbiotas, focusing on how the microbiome may affect treatment efficacy and toxicity and its potential as a therapeutic target to enhance future outcomes.

Microbiotherapy has opened new avenues for managing dysbiosis-related diseases. However, many studies did not cover all the necessary reporting items for microbiotherapy making the interpretation of results, safety assessment, technology extension, and even the transparency of legitimacy difficult. This project consisted of 2 phases. First, we proposed an initial preferred reporting items for microbiotherapy (PRIM) checklist and applied it to oncology studies from 2011 to 2023 according to Meta-Analyses guideline. Only 39.3% (n = 64) of these studies (n = 163) met all PRIM checklist items. The culture-based microbiotherapy (CMT) studies had higher score than non-culture-based (NMT) ones (p = 0.018). In the second phase, the expert panel consisting of 22 specialists from eight countries across Asia, Australia, Europe, and North America refined and finalized the PRIM guidelines (named as PRIM 2024) through Delphi consensus. The PRIM 2024 guidelines conclude 10 statements and 18 points on diagnosis, delivery route, source, classification, preparation, dosage, state, concomitant treatment, efficacy, and safety. The panel defined less than 80% of all PRIM points (14 points) as low-quality reports. These guidelines are recommended for reporting on microbiotherapy in clinical studies and reports on compassionate use, including but not limited to fecal microbiota transplantation, phage therapy, probiotics, and synbiotics. These consistent and transparent reporting items can help researchers and practitioners better evaluate, compare, implement research findings in microbiotherapy.

Fecal microbiota transplantation (FMT) represents a therapeutic approach that directly regulates the gut microbiota of recipients, normalizes its composition and reaping therapeutic rewards. Currently, in addition to its general application in treating Clostridium difficile (C. difficile) infection (CDI), FMT treatment has also been extended to the fields of other gastrointestinal diseases, infections, gut-liver or gut-brain axis disorders, metabolic diseases and cancer, etc. Prior to FMT, rigorous donor screening is essential to reduce the occurrence of adverse events. In addition, it is imperative to evaluate whether the recipient can safely and effectively undergo FMT treatment. However, the efficacy of FMT is influenced by the complex interactions between the gut microbiota of donor and recipient, the degree of donor microbiota engraftment is not necessarily positively related with the success rate of FMT. Furthermore, an increasing number of novel factors affecting FMT outcomes are being identified in recent clinical trials and animal experiments, broadening our understanding of FMT treatment. This article provides a comprehensive review of the application scenarios of FMT, the factors influencing the safety and efficacy of FMT from the aspects of both the donors and the recipients, and summarizes how these emerging novel regulatory factors can be combined to predict the clinical outcomes of patients undergoing FMT.

Cancer immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized oncology, significantly improving survival across multiple cancer types. ICIs, such as anti-PD-1 (e.g. nivolumab, pembrolizumab), anti-PD-L1 (e.g. atezolizumab, avelumab), and anti-CTLA-4 (e.g. ipilimumab), enhance T cell-mediated anti-tumor responses but can also trigger immune-related adverse events (irAEs). Neurological irAEs (n-irAEs), affecting 1-3% of patients, predominantly involve the peripheral nervous system; less commonly, n-irAEs can present as central nervous system disorders. Although irAEs suggest a possible correlation with treatment efficacy, their mechanisms remain unclear, with hypotheses ranging from antigen mimicry to cytokine dysregulation and microbiome alterations. Identifying patients at risk for n-irAEs and predicting their outcome through biomarkers would be highly desirable. For example, patients with high-risk onconeural antibodies (such as anti-Hu or Ma2), and elevated neurofilament light chain (NfL) levels often respond poorly to irAE treatment. However, interpreting neuronal antibody tests in the diagnosis of n-irAEs requires caution: positive results must align with the clinical context, as some cancer patients (e.g., SCLC) may have asymptomatic low antibody levels, and false positive results are common without tissue-based confirmation. Also, the use of biomarkers (e.g. IL-6) may lead to more targeted treatments of irAEs, minimizing adverse effects without compromising the anti-tumor efficacy of ICIs. This review provides a comprehensive overview of the latest findings on n-irAEs associated with ICIs, with a focus on their prediction, prevention, as well as precision treatment using autoantibodies, cytokines, and microbiota. The most interesting data concern neuronal antibodies, which we explore in their pathogenic roles and as biomarkers of neurotoxicity. Most of the available data on cytokines, both regarding their role as diagnostic and prognostic biomarkers and their role in supporting therapeutic decisions for toxicities, refer to non-neurological toxicities. However, in our review, we mention the potential role of CXCL10 and CXCL13 as biomarkers of n-irAEs and describe the current evidence, as well as the need for further studies, on the use of cytokines in guiding selection of second-line therapies for n-irAEs. Finally, no specific microbiome-related microbial signature has been proven to be linked to n-irAEs specifically, leading to the need of more future research on the topic.

Colorectal cancer (CRC) is a major contributor to global cancer-related mortality with increasing incidence rates in both developed and developing regions. Therefore, CRC presents a significant challenge to global health. The development of innovative tools for enhancing early CRC screening and diagnosis, along with novel treatments and therapies for improved management, remains an urgent necessity. CRC is intricately associated with the gut microbiota, which is integral to food digestion, nutrient generation, drug metabolism, metabolite production, immune enhancement, endocrine regulation, neurogenesis modulation, and the maintenance of physiologic and psychological equilibrium. Dysbiosis or imbalances in the gut microbiome have been implicated in various disorders, including CRC. Emerging evidence highlights the critical role of the gut microbiome in CRC pathogenesis and treatment, which presents potential opportunities for early detection and diagnosis. Despite substantial advances in understanding the relationship between the gut microbiota and CRC, significant challenges persist. Gaining a deeper and more detailed understanding of the interactions between the human microbiota and cancer is essential to fully realize the potential of the microbiota in cancer management. Unlike genetic factors, the gut microbiome is subject to modification, offering a promising avenue for the development of CRC treatments and drug discovery. This review provides an overview of the interactions between the human gut microbiome and CRC, while examining prospects for precision management of CRC.

Immune-checkpoint inhibitors (ICIs) enhance the immune response against cancer but can cause immune-related adverse events, with immune-mediated colitis (IMC) being among the most common.

We investigated variations in gastrointestinal disease behavior and outcomes among patients receiving different ICI regimens.

This retrospective chart review included patients who received ICIs and developed IMC. Groups were categorized by their last ICI regimen before IMC onset into either programmed cell death protein-1/ligand-1 monotherapy or cytotoxic T-lymphocyte antigen 4 (CTLA-4) monotherapy/combination immunotherapy. Demographic and IMC-related clinical information was collected.

There were 414 patients included in this study: 169 treated with programmed cell death protein-1/ligand-1 monotherapy and 245 treated with CTLA-4 mono/combination therapy. Patients treated with CTLA-4 therapy had an earlier onset of IMC (median 46 days vs 123 days, p < 0.001). They were more likely to present with fever (p = 0.02), abdominal pain (p = 0.049), or hematochezia (p < 0.001). They also had more severe colitis with 47.3% of patients in the CTLA-4 group presenting with grade ≥3 colitis versus 20.2% in the programmed cell death protein-1/ligand-1 group (p < 0.05). On endoscopy, CTLA-4 mono/combination therapy was associated with increased ulcerative findings (24.4 vs 8.4%, p = 0.002). On histology, the programmed cell death protein-1/ligand-1 group was more likely to have microscopic colitis (13.9 vs 5.8%, p < 0.045).

This study provides insight into the effect of ICI type on IMC disease course. Cytotoxic T-lymphocyte antigen 4 inhibition leads to an earlier and more severe IMC onset with distinct endoscopic and histologic features. Further research is needed to refine treatment algorithms and identify the mechanisms underlying the variability in IMC presentation among different ICI regimens.

Immune checkpoint inhibitors (ICIs) have led to improved outcome in patients with various types of cancer. Due to inhibition of physiological anti-inflammatory mechanisms, patients treated with ICIs may develop autoimmune inflammation of the colon, associated with morbidity, decreased quality of life (QoL), and mortality. In this review, we summarize clinical and pathophysiological aspects of immune-mediated colitis (ImC), highlighting novel treatment options. In the colon, ICIs trigger resident and circulating T cell activation and infiltration of myeloid cells. In addition, the gut microbiota critically contribute to intestinal immune dysregulation and loss of barrier function, thereby propagating local and systemic inflammation. Currently available therapies for ImC include corticosteroids, antitumor necrosis factor-α (TNF-α)- and anti-integrin α4β7 antibodies. Given that systemic immunosuppression might impair antitumor immune responses, novel therapeutic approaches are urgently needed.

Immune checkpoint inhibitors (ICIs) have greatly improved cancer treatment by boosting the immune system's ability to target tumors. However, they can also cause serious side effects, particularly in the digestive system. These include immune-related diarrhea, inflammation of the intestines and, less commonly, inflammation of the stomach or esophagus. This review underscores the importance of early detection, accurate diagnosis, and timely treatment to improve patient outcomes. It also highlights the need for further research to develop strategies to reduce gastrointestinal toxicities and enhance the overall effectiveness of ICIs in cancer therapy.

Cytotoxic T-lymphocyte-associated protein 4 deficiency (CTLA4-D) is an inborn error of immunity (IEI) caused by heterozygous mutations, and characterized by immune cell infiltration into the gut and other organs, leading to intestinal disease, immune dysregulation and autoimmunity. While regulatory T-cell dysfunction remains central to CTLA4-D immunopathogenesis, mechanisms driving disease severity and intestinal pathology are unknown but likely involve intestinal dysbiosis. We determined whether the intestinal microbiome and metabolome could distinguish individuals with severe CTLA4-D and identify biomarkers of disease severity.

The genera Veillonella and Streptococcus emerged as biomarkers that distinguished CTLA4-D from healthy cohorts from both the National Institutes of Health (NIH) Clinical Center, USA (NIH; CTLA-D, n = 32; healthy controls, n = 16), and a geographically distinct cohort from the Center for Chronic Immunodeficiency (CCI) of the Medical Center - University of Freiburg, Germany (CCI; CTLA4-D, n = 25; healthy controls, n = 24). Since IEIs in general may be associated with perturbations of the microbiota, a disease control cohort of individuals with common variable immunodeficiency (CVID, n = 20) was included to evaluate for a CTLA4-D-specific microbial signature. Despite common IEI-associated microbiome changes, the two bacterial genera retained their specificity as biomarkers for CTLA4-D. We further identified intestinal microbiome and metabolomic signatures that distinguished patients with CTLA4-D having severe vs. mild disease. Microbiome changes were associated with distinct stool metabolomic profiles and predicted changes in metabolic pathways. These differences were impacted by the presence of gastrointestinal manifestations and were partially reversed by treatment with abatacept and/or sirolimus.

Loss of intestinal microbial diversity and dysbiosis causing metabolomic changes was observed in CTLA4-D. Albeit some of these features were shared with CVID, the distinct changes associated with CTLA4-D highlight the fact that IEI-associated microbiome changes likely reflect the underlying immune dysregulation. Identified candidate intestinal microbial and metabolic biomarkers distinguishing individuals with CTLA4-D based on severity should be studied prospectively to determine their predictive value, and investigated as potential therapeutic ta. Video Abstract.

Immune checkpoint inhibitors (ICI) have changed the therapeutic landscape of many solid tumors. Modulation of the intestinal microbiota by antibiotics (Abx) has been suggested to impact on ICI outcomes.

Retrospective analysis of 475 patients with advanced solid tumors treated with ICI from 2015 to 2022. For each patient, the use of Abx was recorded from 1 month before ICI initiation until disease progression or death. The impact of Abx on objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS), and overall survival (OS) was analyzed. Kaplan-Meier and log-rank tests were used to compare survival outcomes.

In total 475 patients with advanced solid tumors were evaluated. Median age was 67.5 years and performance status (PS) was 0-1 in 84.6%. 66.5% of patients received Abx during treatment with ICI, mainly beta-lactams (53.8%) and quinolones (35.9%). The early exposure to Abx (from 60 days before to 42 days after the first cycle of ICI) was associated with a lower ORR (27.4% vs 39.4%; P < .01), a lower DCR (37.3% vs 57.4%; P < .001), lower PFS (16.8 m vs 27.8 m; HR 0.66; P < .001]) and lower OS (2.5 m vs 6.6 m; HR 0.68; P = .001]). The negative impact of Abx on OS and PFS was confirmed by a multivariable analysis. This effect was not observed among patients receiving Abx after 6 weeks from ICI initiation.

Our results validate the hypothesis of a detrimental effect of an early exposure to Abxon the efficacy of ICI in a multi-tumor cohort of patients.

Multiple studies have suggested that gut microbiome may influence immune checkpoint inhibitor (ICI) efficacy, but its association with immune-related adverse events (irAEs) is less well studied. In this prospective cohort study, we assessed whether gut microbiome composition at start, or changes during ICI, are associated with severe irAEs.

Stool samples of cancer patients treated with anti-PD-1 ± anti-CTLA-4 were analyzed using 16S rRNA gene sequencing and metagenomic shotgun sequencing. Differences in alpha and beta diversity between patients with and without severe irAE were assessed, as well as differential relative abundance (RA) of taxa, MetaCyc pathways, and seven prespecified literature-based bacterial groups including pathobionts and Ruminococcaceae.

We analyzed 497 samples of 195 patients before and soon after starting ICI, at severe irAE onset and after starting immunosuppression. Mean RA of the pathobionts group was significantly higher in patients who developed a severe irAE (8.2 %) compared to those who did not (4.8 %; odds ratio 1.40; 95 %CI 1.07-1.87) at baseline, and also early during ICI treatment and at severe irAE onset. A significantly stronger decrease in RA of Ruminococcaceae after starting ICI was observed in patients who developed a severe irAE compared to those who did not. RAs of Ruminococcaceae, the genus Ruminococcus, and the species R. bromii and R. callidus were significantly lower at severe irAE onset compared to other time points.

Gut microbiome dysbiosis signaled by higher RA of pathobionts and decrease in RA of Ruminococcaceae may predispose to severe irAEs.

Preclinical and clinical observations indicate that the probiotic Lactobacillus rhamnosus GG (LGG) can modulate colonic inflammation. However, the underlying mechanisms have not been explored in depth. Here, we demonstrate that oral administration of live LGG alleviated inflammatory colitis by increasing IL-10 expression in intestinal Ly6C+ monocytes. Mechanistically, LGG induced IL-10 production via the stimulator of IFN genes (STING)/TBK1/NF-κB (RELA) signaling pathway in intestinal Ly6C+ monocytes, enhancing their immune-suppressive function. Elevated IL-10 subsequently activated IL-10 signaling in Ly6C+ monocytes, resulting in an IL-10-based autocrine regulatory loop and inhibition of proinflammatory cytokine production. Furthermore, LGG shifted the gut microbial community and its metabolic functions, leading to intestinal immune responses against colitis. Fecal microbiota transplantation from LGG-colonized mice alleviated immune checkpoint blockade-associated colitis. Our findings highlight the importance of STING signaling in IL-10-dependent antiinflammatory immunity and establish an empirical basis for developing oral administration of live LGG as an efficient and safe therapeutic strategy against inflammatory colitis.

Immunotherapy has changed the treatment landscape for patients with cancer in the past decade. Immune checkpoint inhibitor (ICI)-based therapies have proven effective in a range of malignancies, including liver and gastrointestinal cancers, but they can cause diverse off-target organ toxicities. With the increasingly wider application of these drugs, immune-mediated liver injury from ICIs has become a commonly encountered challenge in clinical hepatology and gastroenterology. In this Review, we discuss the evidence from human and animal studies on the immunological mechanisms of immune-mediated liver injury from ICIs and summarize its clinical features and practical considerations for its management.

Gut microbiota have been reported to play an important role in the occurrence and development of malignant tumors. Currently, clinical studies have identified specific gut microbiota and its metabolites associated with efficacy of immunotherapy in multiple types of cancers. Preclinical investigations have elucidated that gut microbiota modulate the antitumor immunity and affect the efficacy of cancer immunotherapy. Certain microbiota and its metabolites may favorably remodel the tumor microenvironment by engaging innate and/or adaptive immune cells. Understanding how the gut microbiome interacts with cancer immunotherapy opens new avenues for improving treatment strategies. Fecal microbial transplants, probiotics, dietary interventions, and other strategies targeting the microbiota have shown promise in preclinical studies to enhance the immunotherapy. Ongoing clinical trials are evaluating these approaches. This review presents the recent advancements in understanding the dynamic interplay among the host immunity, the microbiome, and cancer immunotherapy, as well as strategies for modulating the microbiome, with a view to translating into clinical applications.

Inflammatory bowel disease is a chronic inflammatory condition predominantly affecting the intestines, encompassing both ulcerative colitis and Crohn disease (CD). As one of the most common gastrointestinal disorders, CD's pathogenesis is closely linked with the intestinal microbiota. Recently, fecal microbiota transplantation (FMT) has gained attention as a potential treatment for CD, with the effective reestablishment of intestinal microecology considered a crucial mechanism of FMT therapy. This article synthesizes the findings of population-based cohort studies to enhance our understanding of gut microbial characteristics in patients with CD. It delves into the roles of "beneficial" and "pathogenic" bacteria in CD's development. This article systematically reviews and compares data on clinical response rates, remission rates, adverse events, and shifts in bacterial microbiota. Among these studies, gut microbiome analysis was conducted in only 7, and a single study examined the metabolome. Overall, FMT has demonstrated a partial restoration of typical CD-associated microbiological alterations, leading to increased α-diversity in responders and a moderate shift in patient microbiota toward the donor profile. Several factors, including donor selection, delivery route, microbial state (fresh or frozen), and recipient condition, are identified as pivotal in influencing FMT's effectiveness. Future prospective clinical studies with larger patient cohorts and improved methodologies are imperative. In addition, standardization of FMT procedures, coupled with advanced genomic techniques such as macroproteomics and culture genomics, is necessary. These advancements will further clarify the bacterial microbiota alterations that significantly contribute to FMT's therapeutic effects in CD treatment, as well as elucidate the underlying mechanisms of action.

Mitigating climate change in soil ecosystems involves complex plant and microbial processes regulating carbon pools and flows. Here, we advocate for the use of soil microbiome interventions to help increase soil carbon stocks and curb greenhouse gas emissions from managed soils. Direct interventions include the introduction of microbial strains, consortia, phage, and soil transplants, whereas indirect interventions include managing soil conditions or additives to modulate community composition or its activities. Approaches to increase soil carbon stocks using microbially catalyzed processes include increasing carbon inputs from plants, promoting soil organic matter (SOM) formation, and reducing SOM turnover and production of diverse greenhouse gases. Marginal or degraded soils may provide the greatest opportunities for enhancing global soil carbon stocks. Among the many knowledge gaps in this field, crucial gaps include the processes influencing the transformation of plant-derived soil carbon inputs into SOM and the identity of the microbes and microbial activities impacting this transformation. As a critical step forward, we encourage broadening the current widespread screening of potentially beneficial soil microorganisms to encompass functions relevant to stimulating soil carbon stocks. Moreover, in developing these interventions, we must consider the potential ecological ramifications and uncertainties, such as incurred by the widespread introduction of homogenous inoculants and consortia, and the need for site-specificity given the extreme variation among soil habitats. Incentivization and implementation at large spatial scales could effectively harness increases in soil carbon stocks, helping to mitigate the impacts of climate change.

Immune checkpoint inhibitors (ICIs) have transformed oncological treatment by modulating immune responses against tumors. However, their efficacy is subject to inter-patient variability and is associated with immune-related adverse events (irAEs). The human gut microbiota, a complex microbial ecosystem, is increasingly implicated in modulating responses to ICIs. This bibliometric analysis examines the 100 most-cited articles to elucidate trends and advancements in research concerning the gut microbiota's impact on ICI efficacy.

A systematic literature retrieval was conducted within the Web of Science Core Collection (WoSCC), focusing on the 100 most-cited articles. VOSviewer and CiteSpace were utilized for bibliometric analysis, examining collaborative patterns and keyword co-occurrences. The relationship between citing and cited entities was analyzed, and burst ranking identified research hotspots based on citation frequency.

The 100 most-cited publications encompassed a range of disciplines, with a predominance of oncological research. The United States and China were leading in publication volume, with France and Canada also contributing significantly. French institutions, particularly INSERM and Université Paris Cite, were prolific. Routy, Bertrand and Zitvogel, Laurence were prominent among high-impact authors. Dominant keywords included "gut microbiota," "immunotherapy," "efficacy," and "cancer." The article by Routy et al. (2018) was the most frequently cited.

This study highlights the significant role of the gut microbiota in ICI development and efficacy, emphasizing the necessity for international and interdisciplinary collaboration. The research is progressively focusing on managing immunotherapy side effects and optimizing treatment strategies. Challenges, including individual variability in gut microbiota composition, persist. Further research is imperative to exploit the potential of the gut microbiota in cancer therapy, advocating for personalized approaches and a more profound comprehension of the underlying mechanisms.

Immunotherapy-related colitis (irC) frequently emerges as an immune-related adverse event during immune checkpoint inhibitor therapy and is presumably influenced by the gut microbiota. We longitudinally studied microbiomes from 38 ICI-treated cancer patients. We compared 13 ICI-treated subjects who developed irC against 25 ICI-treated subjects who remained irC-free, along with a validation cohort. Leveraging a preclinical mouse model, predisease stools from irC subjects induced greater colitigenicity upon transfer to mice. The microbiota during the first 10 days of irC closely resembled inflammatory bowel disease microbiomes, with reduced diversity, increased Proteobacteria and Veillonella, and decreased Faecalibacterium, which normalized before irC remission. These findings highlight the irC gut microbiota as functionally distinct but phylogenetically similar to non-irC and healthy microbiomes, with the exception of an acute, transient disruption early in irC. We underscore the significance of longitudinal microbiome profiling in developing clinical avenues to detect, monitor, and mitigate irC in ICI therapy cancer patients.

Immune checkpoint inhibitors commonly cause gastrointestinal immune-related adverse effects. These patients also carry an increased risk of concomitant infections. This 66-year-old man with immune checkpoint inhibitor colitis was discovered to have concurrent Yersinia and Cytomegalovirus colitis. Such infections may mimic or complicate disease course. Hence, clinicians must monitor patient symptoms, have a low threshold for infectious testing and colonoscopy, and consider treatment strategies to mitigate their risk.

Cancer is one of the most difficult diseases facing modern medicine, and increasing amounts of research and clinical treatments are being applied to the treatment of cancer. Immunotherapy, particularly immune checkpoint inhibitor (ICI) therapy, has revolutionized the treatment and overall survival of patients with several different types of cancer. Approximately one-third of patients treated with ICIs may experience immune-related adverse events (irAEs). Immune checkpoint inhibitor-associated colitis (ICIC) is the most common irAE with an incidence of approximately 8-10%, ICIC usually presents as watery or bloody diarrhea, and if the symptoms are severe, ICI treatment must be interrupted or even terminated. This review summarizes the epidemiology, pathogenesis, clinical characteristics, and therapies of ICIC, focusing on the use of biologics, in order to propose treatment options in different situations to control immune checkpoint inhibitor-related colitis as soon as possible.

To find relevant articles for this narrative review paper, a combination of keywords such as immune checkpoint inhibitor-related colitis, corticosteroids, biologics were searched for in PubMed databases.

The pathogenesis of ICIC is complex and primarily involves antitumor effects and indirect damage to colonic tissues, as well as the activation of specific proinflammatory pathways. Corticosteroids (CSs) are the first line of treatment for ICIC, but steroid-refractory or steroid-resistant cases often occur. Patients with irAE colitis respond favorably to biologics, and patients with CS-resistant/refractory enterocolitis can benefit from the early use of biologics.

Biologics are currently recommended for the treatment of ICIC but are usually used as a supplement after the failure of first-line CS therapy. Patients with irAE colitis respond favorably to biologics, and patients with CS-resistant/refractory enterocolitis can benefit from the early use of biologics. Biologics (alone or in combination with CS) should be considered as an early therapy option for high-risk patients rather than just an escalation after a failure to respond to CS.

Cancer remains a global problem, with millions of new cases diagnosed yearly and countless lives lost. The financial burden of cancer therapy, along with worries about the long-term safety of existing medicines, necessitates the investigation of alternative approaches to cancer prevention. Probiotics generate chemopreventive compounds such as bacteriocins, short-chain fatty acids (SCFA), and extracellular polymeric substances (EPS), which have demonstrated the ability to impede cancer cell proliferation, induce apoptosis, and bolster the expression of pro-apoptotic genes. On the other hand, prebiotics, classified as non-digestible food ingredients, promote the proliferation of probiotics within the colon, thereby ensuring sustained functionality of the gut microbiota. Consequently, the synergistic effect of combining prebiotics with probiotics, known as the synbiotic effect, in dietary interventions holds promise for potentially mitigating cancer risk and augmenting preventive measures. The utilization of gut microbiota in cancer treatment has shown promise in alleviating adverse health effects. This review explored the potential and the role of probiotics and synbiotics in enhancing health and contributing to cancer prevention efforts. In this review, the applications of functional probiotics and synbiotics, the mechanisms of action of probiotics in cancer, and the relationship of probiotics with various drugs were discussed, shedding light on the potential of probiotics and synbiotics to alleviate the burdens of cancer treatment.