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.

Over the last decade, the increasing global prevalence of melanoma has sparked growing interest in immunotherapies, which show significant potential against this form of skin cancer. This research aims to offer a framework to guide future studies and inspire new research directions. In this study, we used the Web of Science Core Collection to collect papers on immunotherapy and melanoma published between 2014 and 2024. With Excel and visualization tools like VOSviewer, COOC 13.2, Citespace, and Bibliometrix (R-Tool of R-Studio), we analyzed the data to spot trends and new focuses in the research. Our findings indicate a substantial surge in research activity concerning immunotherapy and melanoma between 2014 and 2024. The USA and China emerged as leading contributors, engaging in extensive and close collaborative efforts with European counterparts. Furthermore, seven of the top 10 research institutions are located in the USA, with the MD Anderson Cancer Center in Texas being the most productive. In addition, the Journal of Cancer Immunotherapy is the journal with the most articles published in the field. Professor Georgina V. Long from the Melanoma Institute at the University of Sydney was one of the most productive scholars. Keyword analysis shows that immune checkpoint inhibitors, tumor microenvironment and targeted therapies are key areas of interest for the research community. This paper uses bibliometric analysis to outline research trends and key points in immunotherapy and melanoma from 2014 to 2024, which helps understand the current research and guides future research directions.

The human microbiome plays a pivotal role in the field of cancer immunotherapy. The microbial communities that inhabit the gastrointestinal tract, as well as the bacterial populations within tumors, have been identified as key modulators of therapeutic outcomes, affecting immune responses and reprogramming the tumor microenvironment. Advances in synthetic biology have made it possible to reprogram and engineer these microorganisms to improve antitumor activity, enhance T-cell function, and enable targeted delivery of therapies to neoplasms. This review discusses the role of the microbiome in modulating both innate and adaptive immune mechanisms-ranging from the initiation of cytokine production and antigen presentation to the regulation of immune checkpoints-and discusses how these mechanisms improve the efficacy of immune checkpoint inhibitors. We highlight significant advances with bioengineered strains like Escherichia coli Nissle 1917, Lactococcus lactis, Bifidobacterium, and Bacteroides, which have shown promising antitumor efficacy in preclinical models. These engineered microorganisms not only efficiently colonize tumor tissues but also help overcome resistance to standard therapies by reprogramming the local immune environment. Nevertheless, several challenges remain, such as the requirement for genetic stability, effective tumor colonization, and the control of potential safety issues. In the future, the ongoing development of genetic engineering tools and the optimization of bacterial delivery systems are crucial for the translation of microbiome-based therapies into the clinic. This review highlights the potential of bioengineered microbiota as an innovative, personalized approach in cancer immunotherapy, bringing hope for more effective and personalized treatment options for patients with advanced malignancies.

The anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 antibody ipilimumab (ipi) and the anti-programmed death (PD)-1 antibody nivolumab (nivo) are routinely used to treat metastatic melanoma. One of the most frequent severe immune-related adverse events (irAEs) induced by ipi is diarrhea as a symptom of ir-colitis. Here, the composition of the gut microbiome was shown to correlate with the risk of developing colitis. Stimulated by a patient case and the knowledge that nutrition influences the gut microbiome, we performed a retrospective analysis to evaluate dietary habits and the frequency of colitis in patients with ipi ± nivo therapy.

Patients with metastasized stage III or IV melanoma who were treated with ipi ± nivo and who were willing to take part in a nutritional survey and interview at least three months after the first ipi dose were included into the study. Dietary habits were investigated using the food frequency questionnaire (FFQ) and personal interviews. The calculated daily intake of calories, carbohydrates, fats, proteins, sugars, and dietary fiber was correlated with the development of ir-colitis.

20 patients were included into this study, and all but one received ipi-nivo combination therapy. The median age was 59.5 years, and 60 % were male. 4 of 20 patients (20 %) developed ir-colitis grade 3 after two cycles in the median and were managed with at least high-dose corticosteroids. The FFQ and interview were conducted in a median of six months after treatment initiation. In general, the interviewed patients followed a typical western-pattern diet based on carbohydrates as the main, followed by fat as the second most important energy substrate. Comparing patients with and without colitis our investigation revealed that the achieved amount of recommended dietary fiber intake per total energy intake (TEI) was negatively associated with diarrhea and colitis (p = 0.061). No significant differences concerning daily intake of calories, carbohydrates, fats, proteins, and sugar were found. In addition, no significant differences were found among patients in terms of their age, gender, tobacco use, supplement intake, therapy regime, or body mass index (BMI).

This pilot study gives first hints that nutritional habits might influence treatment tolerability to ipi ± nivo therapy. A high-fiber diet might protect against ir-colitis and diarrhea in ipi-treated patients. This observation should be validated by a prospective randomized interventional trial. However, if it is possible to prevent ir-colitis by a high-fiber diet that would be of great impact on routine patient treatment.

Immune system plays a crucial role in the physiological and pathological regulation of the cardiovascular system. The exploration history and milestones of immune system in cardiovascular diseases (CVDs) have evolved from the initial discovery of chronic inflammation in atherosclerosis to large-scale clinical studies confirming the importance of anti-inflammatory therapy in treating CVDs. This progress has been facilitated by advancements in various technological approaches, including multi-omics analysis (single-cell sequencing, spatial transcriptome et al.) and significant improvements in immunotherapy techniques such as chimeric antigen receptor (CAR)-T cell therapy. Both innate and adaptive immunity holds a pivotal role in CVDs, involving Toll-like receptor (TLR) signaling pathway, nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1/2) signaling pathway, inflammasome signaling pathway, RNA and DNA sensing signaling pathway, as well as antibody-mediated and complement-dependent systems. Meanwhile, immune responses are simultaneously regulated by multi-level regulations in CVDs, including epigenetics (DNA, RNA, protein) and other key signaling pathways in CVDs, interactions among immune cells, and interactions between immune and cardiac or vascular cells. Remarkably, based on the progress in basic research on immune responses in the cardiovascular system, significant advancements have also been made in pre-clinical and clinical studies of immunotherapy. This review provides an overview of the role of immune system in the cardiovascular system, providing in-depth insights into the physiological and pathological regulation of immune responses in various CVDs, highlighting the impact of multi-level regulation of immune responses in CVDs. Finally, we also discuss pre-clinical and clinical strategies targeting the immune system and translational implications in CVDs.

Metformin is frequently prescribed to treat type 2 diabetes. Its primarily regulates hepatic and colonic glucose metabolism, but recent studies have suggested an anti-inflammatory effect, especially in colitis. It has been suggested that metformin may enhance immune checkpoint inhibition (ICI) efficacy for cancer treatment. Our study aims to explore the impact of metformin on ICI efficacy and the risk for colitis.

This was a single center, retrospective analysis of consecutive patients at a tertiary cancer center who received ICI between 01/2010-12/2022 and developed immune-mediated colitis (IMC). Patients were screened for colitis based on stool tests, then divided into two groups depending on metformin use prior to colitis onset. We collected data on demographic and colitis clinical information including treatments, and outcomes.

A total of 953 patients were included. The incidence of IMC was higher among metformin users (7.6 %) than non-metformin users (4.9 %; p < 0.01). There were no significant differences in colitis features and outcomes, except for longer hospital stay among metformin users (8 days vs 6 for non-metformin users; p = 0.03). Metformin use was associated with shorter overall survival vs non-metformin users among patients with IMC (p = 0.03).

Our study is among the first to explore the impact of metformin on IMC and overall survival. We found that metformin use may be associated with higher risk of IMC. We also found an association between metformin use and shorter overall survival among patients who developed IMC. Larger studies with risk-stratified analysis are needed to validate our findings.

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.

Immune checkpoint inhibitors (ICI) boost the endogenous anticancer immunity, evoking long-lasting anticancer responses in a subset of patients with solid tumors. Simultaneously, ICI are also associated with serious toxicities, impacting treatment duration and the quality of life. The proposed processes underlying ICI-related toxicity include T-cell activation and recruitment to non-tumor tissues, involvement of other immune cells and fibroblasts and the host' microbiome composition. However, the exact mechanisms of these processes remain incompletely understood, hindering clinicians' ability to predict and identify ICI-related toxicity in the early stages of treatment. Molecular imaging may play a role as a non-invasive biomarker, providing a tool to study ICI-related toxicity. This review discusses the applications of molecular imaging to answer questions regarding the mechanisms, detection, and prediction of ICI-related toxicity. Potential targets and the current state of development of suitable imaging techniques are discussed.

The limited understanding of microbial response mechanism remains as a bottleneck to evaluate the long-term remediation effectiveness of in situ chemical oxidation in contaminated groundwater. In this study, we investigated long-term response of bacterial communities throughout five remediation stages of pre-oxidation, early-oxidation, late-oxidation, early-recovery and late-recovery. By analyzing bacterial biomass, taxa, diversity and metabolic functions, this work identified the consistently suppressed glyceraldehyde-3-phosphate dehydrogenase pathway and the enrichment of naphthalene degradation pathways for secondary products, suggesting persistent oxidation stress and enhanced microbial utilization of lower-molecular weight carbon sources at the oxidation and early-recovery stages. The dominant microbial clusters shifted from r-strategists to K-strategists and then back to r-strategists, indicating their higher degradation efficiency of petroleum hydrocarbons throughout the oxidation process. The changes in stability and stochastic assembly of bacterial communities during in situ chemical oxidation suggested that oxidative stress, carbon source addition and carbon source limitation as the main influential factors of bacterial community succession at the oxidation, early-recovery and late-recovery stage, respectively. Our findings highlighted the complex recovery and underlying mechanisms of groundwater bacterial communities during in situ chemical oxidation process, and provided valuable insights for effective and long-term site management after in situ chemical oxidation practices.

With their groundbreaking clinical responses, immune checkpoint inhibitors (ICIs) have ushered in a new chapter in cancer therapeutics. However, they are often associated with life-threatening or organ-threatening autoimmune/autoinflammatory phenomena, collectively termed immune-related adverse events (irAEs). In this review, we will first describe the mechanisms of action of ICIs as well as irAEs. Next, we will review biomarkers for predicting the development of irAEs or stratifying risks.

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.

Tumor displays various forms of tumor heterogeneity including immune heterogeneity that allow cancer cells to survive during conventional anticancer drug interventions. Thus, there is a strong rationale for overcoming anticancer drug resistance by employing the components of immune cells. Using the immune system to target tumor cells has revolutionized treatment. Recently, significant progress has been achieved at preclinical and clinical levels to benefit cancer patients.

A review of literature from the past ten years across PubMed, Scopus, and Web of Science focused on immunotherapy strategies. These include immune checkpoint inhibitors (ICIs), tumor-infiltrating lymphocyte therapy, antibody-drug conjugates (ADCs), cancer vaccines, CAR T-cell therapy, and the role of the gut microbiome.

While immunotherapy outcomes have improved, particularly for tumor types such as melanoma and non-small cell lung cancer (NSCLC), challenges persist regarding predictive biomarker identification and better management. Ongoing research on modifiers of immune function like gut microbiome-derived metabolites, next-generation ADCs, and new classes of biologics is warranted. Overall, continued investigation toward optimizing synergistic immunotherapeutic combinations through strategic drug delivery systems is imperative for preclinical and clinical success in cancer patients.

This review discusses reprogramming the breast tumor immune microenvironment from an immunosuppressive cold state to an immunologically active hot state. A complex interplay is revealed, in which the accumulation of metabolic byproducts-such as lactate, reactive oxygen species (ROS), and ammonia-is shown to impair T-cell function and promote tumor immune escape. It is demonstrated that the tumor microenvironment (TME) is dominated by immunosuppressive cytokines, including interleukin-10 (IL-10), transforming growth factorβ (TGFβ), and IL-35. Notably, IL-35 is produced by regulatory T cells and breast cancer cells. The conversion of conventional T cells into IL-35-producing induced regulatory T cells, along with the inhibition of pro-inflammatory cytokine secretion, contributes to the suppression of anti-tumor immunity. It is further demonstrated that key immune checkpoint molecules-such as PD-1, PDL1, CTLA-4, TIM-3, LAG-3, and TIGIT-are upregulated within the TME, leading to Tcell exhaustion and diminished immune responses. The blockade of these checkpoints is shown to restore T-cell functionality and is proposed as a strategy to convert cold tumors into hot ones with robust effector cell infiltration. The therapeutic potential of chimeric antigen receptor (CAR)T cell therapy is also explored, and targeting specific tumor-associated antigens, such as glycoproteins and receptor tyrosine kinases, is highlighted. It is suggested that CART cell efficacy can be enhanced by combining these cells with immune checkpoint inhibitors and other immunomodulatory agents, thereby overcoming the barriers imposed by the immunosuppressive TME. Moreover, the role of the microbiome in regulating estrogen metabolism and systemic inflammation is reviewed. Alterations in the gut microbiota are shown to affect the TME, and microbiome-based interventions are proposed as an additional means to facilitate the cold-to-hot transition. It is concluded that by targeting the metabolic and immunological pathways that underpin immune suppression-through combination strategies involving checkpoint blockade, CART cell therapies, and microbiome modulation-the conversion of the breast TME from cold to hot can be achieved. This reprogramming is anticipated to enhance immune cell infiltration and function, thereby improving the overall efficacy of immunotherapies and leading to better clinical outcomes for breast cancer patients.

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.

Diet impacts cancer in diverse manners. Multiple nutritional effects on tumors are mediated by dietary modulation of commensals, residing in mucosal surfaces and possibly also within the tumor microenvironment. Mechanistically understanding such diet-microbiome-host interactions may enable to develop precision nutritional interventions impacting cancer development, dissemination, and treatment responses. However, data-driven nutritional strategies integrating diet-microbiome interactions are infrequently incorporated into cancer prevention and treatment schemes. Herein, we discuss how dietary composition affects cancer-related processes through alterations exerted by specific nutrients and complex foods on the microbiome. We highlight how dietary timing, including time-restricted feeding, impacts microbial function in modulating cancer and its therapy. We review existing and experimental nutritional approaches aimed at enhancing microbiome-mediated cancer treatment responsiveness while minimizing adverse effects, and address challenges and prospects in integrating diet-microbiome interactions into precision oncology. Collectively, mechanistically understanding diet-microbiome-host interactomes may enable to achieve a personalized and microbiome-informed optimization of nutritional cancer interventions.

In the last years, we assisted to a tremendous increase in therapeutic options for the management of cancers, with immunotherapy at the forefront of this innovation. Immune checkpoint inhibitors (ICIs) have been developed to enhance the activity of the immune system against cancer cells (1) and the number of approvals for ICIs has rapidly increased. ICIs have also been associated with disinhibited cytotoxic T cells that damage healthy tissue in multiple organs, causing immune-related adverse events (AEs). Cardiovascular AEs (CVAe) are increasingly reported: myocarditis, Takotsubo syndrome, pericarditis and pericardial effusion, worsening of atherosclerosis, acute coronary syndromes, non-inflammatory heart failure, and ischaemic stroke. They are classified into five grades, based on presenting symptoms, level of cardiac biomarkers, and imaging. Even though myocarditis occurs more frequently than previously thought, clinically relevant myocarditis is a rare irAE compared to other irAE (0.5-1.2%). The clinical manifestations range from mild symptoms such as to chest pain, heart failure, and cardiogenic shock. The prognosis is severe, with mortality rates ranging from 25% to 50%. It is frequently associated with the concomitant use of combination of checkpoint inhibitors. The treatment strategies are tripartite: (i) holding ICI to prevent further toxicity, (ii) immunosuppression to alleviate inflammatory changes, and (iii) supportive therapy to address cardiac complications. Glucocorticoids represent the first-line treatment. In hemodynamically unstable patients, treatment with high-dose steroids should be initiated (intravenous methylprednisolone 1000 or 1250 mg oral methylprednisolone during 4 days). ICI-associated pericarditis can be accompanied by no/mild pericardial effusion up to cardiac tamponade. The treatment is made of nonsteroidal anti-inflammatory drugs and colchicine, corticosteroids if needed, and pericardiocentesis for the large effusions. ICIs could be continued for Grade 1 pericarditis, while temporary suspension of ICI is warranted for more severe cases. There is significant potential for accelerated atherosclerosis with ICIs as a long-term effect, but atherosclerosis-related CVAEs are not frequent, especially during treatment; increasing evidence associates ICIs with progression of atherosclerosis and increased atherosclerotic cardiovascular disease. ICIs can lead to arrhythmias: atrial fibrillation, supraventricular and ventricular tachycardias. Non-inflammatory heart failure syndrome have been observed in ICI-treated patients. Immune checkpoint inhibitors seem to be involved in the development of right ventricular dysfunction and pulmonary arterial hypertension. It is of the outmost importance to improve the collaboration among the different medical figures, such as cardiologists, oncologists, endocrinologists, and immunologists, both in clinical practice and in basic science research, to better recognize these adverse events, to understand their pathophysiological mechanisms, and to improve the overall survival and quality of life of the affected patients.

Our primary objective was to estimate the overall response rate to immune checkpoint inhibitors (ICIs) in patients with locally advanced, multiply recurrent, or metastatic conjunctival melanoma treated with ICIs. A retrospective review of all consecutive conjunctival melanoma patients who were treated with ICI between October 2017 and January 2024 was carried out. The study included 16 patients with a median age of 66 years. The indications for ICI were locally extensive conjunctival melanoma in the eye/orbital area without nodal or distant metastasis in 10 patients, local recurrence of conjunctival melanoma and simultaneous nodal or distant metastasis in four patients, and metastatic conjunctival melanoma without local recurrence in two patients. Five patients received PD-1 inhibitor monotherapy with nivolumab or pembrolizumab; the other 11 received ipilimumab (CTLA-4 inhibitor) and nivolumab for several cycles and were then continued on nivolumab monotherapy ( n = 6) or not given additional ICI therapy ( n = 3). The number of cycles of ICI ranged from 2 to 25 (median, 13). Eight patients achieved a complete response. Six patients had progressive disease. The overall rate of objective response to ICI therapy was 63% (10 of 16), and for the subset of patients with local disease only, the objective response rate was 70% (7 of 10). In 14 patients (88%), orbital exenteration or additional extensive surgery was avoided; two patients had progression despite ICI and eventually needed an orbital exenteration. Future studies should aim to correlate biomarker data with response to ICI therapy in patients with conjunctival melanoma.

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.

Significant sex-based differences exist in the immune system and antitumor immune responses, potentially leading to variations in both the efficacy and toxicity of anticancer immunotherapies. Women generally mount stronger innate and adaptive immune responses than men, which can result in more severe immune-related adverse events (irAEs) during treatments with immune checkpoint inhibitors (ICIs). However, the importance of sex dimorphism in the safety of cancer immunotherapy remains underexplored in clinical oncology, despite its profound implications for treatment outcomes. Our review highlights the critical influence of biological sex on pharmacokinetics, pharmacodynamics, and immune responses, shaping ICI efficacy and the prevalence, type, and severity of irAEs. Integrating sex as a critical variable in cancer treatment and clinical trial design is essential for personalizing therapeutic strategies, bridging existing knowledge gaps, and enhancing survival rates and quality of life for patients across genders.

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.

In order to decipher the relationship between gut microbiota imbalance and cancer, this paper reviewed the role of intestinal microbiota in anticancer therapy and related mechanisms, discussed the current research status of gut microbiota as a biomarker of cancer, and finally summarized the reasonable means of regulating gut microbiota to assist cancer therapy. Overall, our study reveals that the gut microbiota can serve as a potential target for improving cancer management.

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.

The emergence of cancer immunotherapy has revolutionized cancer treatment, offering remarkable outcomes for patients across various malignancies. However, the heterogeneous response to immunotherapy underscores the necessity of understanding additional factors influencing treatment efficacy. Among these factors, the human microbiota has garnered significant attention for its potential role in modulating immune response. Body: This review explores the intricate relationship between the human microbiota and cancer immunotherapy, highlighting recent advances and potential mechanisms underlying microbial influence on treatment outcomes.

Insights into the microbiome's impact on immunotherapy response not only deepen our understanding of cancer pathogenesis but also hold promise for personalized therapeutic strategies aimed at optimizing patient outcomes.

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.

Ibrutinib, a widely used anti-cancer drug, is known to significantly increase the susceptibility to atrial fibrillation (AF). While it is recognized that drugs can reshape the gut microbiota, influencing both therapeutic effectiveness and adverse events, the role of gut microbiota in ibrutinib-induced AF remains largely unexplored.

Utilizing 16S rRNA gene sequencing, faecal microbiota transplantation, metabonomics, electrophysiological examination, and molecular biology methodologies, we sought to validate the hypothesis that gut microbiota dysbiosis promotes ibrutinib-associated AF and to elucidate the underlying mechanisms.

We found that ibrutinib administration pre-disposes rats to AF. Interestingly, ibrutinib-associated microbial transplantation conferred increased susceptibility to AF in rats. Notably, ibrutinib induced a significantly decrease in the abundance of Lactobacillus gasseri (L. gasseri), and oral supplementation of L. gasseri or its metabolite, butyrate (BA), effectively prevented rats from ibrutinib-induced AF. Mechanistically, BA inhibits the generation of reactive oxygen species, thereby ameliorating atrial structural remodelling. Furthermore, we demonstrated that ibrutinib inhibited the growth of L. gasseri by disrupting the intestinal barrier integrity.

Collectively, our findings provide compelling experimental evidence supporting the potential efficacy of targeting gut microbes in preventing ibrutinib-associated AF, opening new avenues for therapeutic interventions.

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.

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.

The human microbiome has garnered tremendous interest in the field of oncology, and microbiota studies in head and neck oncology has also flourished. Given the increasing incidence and mortality of HNSCC, as well as the suboptimal outcomes of available treatments, there is an urgent need for innovative approaches involving the microbiome. This review evaluates the intricate relationship between the microbiome and HNSCC, highlighting the potential of the microbiome as a marker for cancer detection, its role in malignancy, and its impact on the efficacy of conventional treatments like chemotherapy and radiotherapy. The review also explores the effects of treatment modalities on the microbiome and discusses the potential of microbiome alterations to predict and influence treatment toxicities such as mucositis and xerostomia. Further research is warranted to characterize the microbiome-HNSCC association, which holds promise for advancing early diagnosis, enhancing prognostic accuracy, and personalizing treatment strategies to improve patient outcomes. The exploration of the microbiome in clinical trials indicates a burgeoning subject of microbiome-focused therapies, heralding a new frontier in most cancer care.

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.

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.

The gut microbiota, a dynamic ecosystem of trillions of microorganisms, produces secondary metabolites that profoundly influence host health. Recent research has highlighted the significant role of these metabolites, particularly short-chain fatty acids, indoles, and bile acids, in modulating immune responses, impacting epigenetic mechanisms, and contributing to disease processes. In gastrointestinal (GI) cancers such as colorectal, liver, and gastric cancer, microbial metabolites can drive tumorigenesis by promoting inflammation, DNA damage, and immune evasion. Conversely, these same metabolites hold therapeutic promise, potentially enhancing responses to chemotherapy and immunotherapy and even directly suppressing tumor growth. In addition, gut microbial metabolites play crucial roles in infectious disease susceptibility and resilience, mediating immune pathways that impact pathogen resistance. By consolidating recent insights into the gut microbiota's role in shaping disease and health, this review underscores the therapeutic potential of targeting microbiome-derived metabolites for treating GI cancers and infectious diseases and calls for further research into microbiome-based interventions.

Effective biomarkers for assessing anti-PD-1/PD-L1 therapy efficacy in patients with nasopharyngeal carcinoma (NPC) are still lacking. The human gut microbiota has been shown to influence clinical response to anti-PD-1/PD-L1 therapy in many cancers. However, the relationship between the gut microbiota and the efficacy of immunotherapy in patients with nasopharyngeal carcinoma has not been determined.

We conducted a prospective study in which fecal and blood samples from patients with NPC were subjected to 16S rDNA sequencing and survival analysis. To investigate potential differences in the gut microbiome between these groups and to identify potential biomarkers indicative of immunotherapy efficacy, patients were categorized into two groups according to their clinical response to immunotherapy, the responder group (R group) and the non-responder group (NR group). Progression-free survival (PFS) between these subgroups was analyzed using Kaplan-Meier survival analysis with the log-rank test. Additionally, we performed univariate and multivariate analyses to evaluate prognostic factors. Finally, we carried out non-targeted metabolomics to examine the metabolic effects associated with the identified microbiome.

Our 16S rDNA sequencing results showed that the abundance of Lachnoclostridium was higher in the NR group than in the R group (p = 0.003), and alpha diversity analysis showed that the abundance of microbiota in the NR group was higher than that in the R group (p = 0.050). Patients with a lower abundance of Lachnoclostridium had better PFS (p = 0.048). Univariate (p = 0.017) and multivariate analysis (p = 0.040) showed that Lachnoclostridium was a predictor of PFS. Non-targeted metabolomics analysis revealed that Lachnoclostridium affects the efficacy of immunotherapy through the usnic acid.

High abundance of Lachnoclostridium predicts poor prognosis in patients with NPC receiving immunotherapy.

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.

Gastrointestinal (GI) toxicities are among the most common and potentially severe immune-related adverse events (irAEs), and data on risk factors remain limited. This study aimed to identify risk factors for GI-irAEs in patients treated with ICIs.

We conducted a retrospective analysis of patients with any type of malignant tumor who received ICIs between January 2020 and January 2022. GI-irAEs were defined as the onset of diarrhea during the observation period. Univariate analysis was employed to explore associations between GI-irAEs and patient characteristics.

Of the 485 patients screened, 361 were eligible for analysis. GI-irAEs occurred in 29 patients (8.03%). Patients with GI cancer demonstrated shorter event-free survival (EFS) compared to those with non-GI cancer (2.33, 95% CI: 1.03-4.95; p = 0.0275). Additionally, ≥ grade 2 GI-irAEs were observed in 14 patients (3.88%). Patients with GU cancer had a significantly higher incidence of GI-irAEs (odds ratio: 3.26, 95%CI 1.21-8.71, p = 0.0497) and exhibited shorter EFS (hazard ratio: 3.07, 95%CI: 1.05-8.96; p = 0.0273) compared to those with non-GU cancer.

Our findings suggest that GI cancer may be a risk factor for developing GI-irAEs, while GU cancer may predispose patients to ≥ grade 2 GI-irAEs.

Microbiomes occupy a range of niches and, in addition to having diverse compositions, they have varied functional roles that have an impact on agriculture, environmental sciences, and human health and disease. The study of microbiomes has been facilitated by recent technological and analytical advances, such as cheaper and higher-throughput DNA and RNA sequencing, improved long-read sequencing and innovative computational analysis methods. These advances are providing a deeper understanding of microbiomes at the genomic, transcriptional and translational level, generating insights into their function and composition at resolutions beyond the species level.