Liver cancer is usually diagnosed at an advanced stage and is the third most common cause of cancer-related death worldwide. In addition to the lack of effective treatment options, resistance to therapeutic drugs is a major clinical challenge. The gut microbiota has recently been recognized as one of the key factors regulating host health. The microbiota and its metabolites can directly or indirectly regulate gene expression in the liver, leading to gut-liver axis dysregulation, which is closely related to liver cancer occurrence and the treatment response. Gut microbiota disturbance may participate in tumor progression and drug resistance through metabolite production, gene transfer, immune regulation, and other mechanisms. However, systematic reviews on the role of the gut microbiota in drug resistance in liver cancer are lacking. Herein, we review the relationships between the gut microbiota and the occurrence and drug resistance of hepatocellular carcinoma, summarize the emerging mechanisms underlying gut microbiota-mediated drug resistance, and propose new personalized treatment options to overcome this resistance.

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 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.

Over the past 3 years, there has been a growing interest in clinical research regarding the potential involvement of intestinal flora in thyroid cancer (TC). This review delves into the intricate connection between intestinal flora and TC, focusing on the particular intestinal flora that is directly linked to the disease and identifying which may be able to predict potential microbial markers of TC. In order to shed light on the inflammatory pathways connected to the onset of TC, we investigated the impact of intestinal flora on immune modulation and the connection between chronic inflammation when investigating the role of intestinal flora in the pathogenesis of TC. Furthermore, the potential role of intestinal flora metabolites in the regulation of thyroid function was clarified by exploring the effects of short-chain fatty acids and lipopolysaccharide on thyroid hormone synthesis and metabolism. Based on these findings, we further explore the effects of probiotics, prebiotics, postbiotics, vitamins, and trace elements.

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.

Growing evidence suggests that microbes located within the gastrointestinal tract and other anatomical locations influence the development and progression of diseases such as cancer.

Clinical and preclinical evidence suggests that microbes in the gastrointestinal tract and other anatomical locations, such as the respiratory tract, may affect carcinogenesis, development of metastases, cancer treatment response, and cancer treatment-related adverse effects. Within tumors of patients with cancer, microbes may affect response to treatment, and therapies that reduce or eliminate these microbes may improve outcomes in patients with cancer. Modulating gastrointestinal tract (gut) microbes through fecal microbiota transplant and other strategies such as dietary intervention (eg, high-fiber diet intervention) has improved outcomes in small studies of patients treated with cancer immunotherapy. In contrast, disruption of the gut microbiota by receipt of broad-spectrum antibiotics prior to treatment with cancer immunotherapy has been associated with poorer overall survival and higher rates of adverse effects in patients treated with immune checkpoint blockade for solid tumors and also with chimeric antigen receptor T-cell therapy for hematologic malignancies.

Microbes in the gut and other locations in the body may influence the development and progression of cancer and may affect the response to adverse effects from cancer therapy. Future therapies targeting microbes in the gut and other locations in the body could potentially improve outcomes in patients with cancer.

Interindividual variability in drug exposure can significantly influence treatment outcomes and may lead to drug concentration-related side effects during tuberculosis (TB) treatment. Although the gut microbiota is known to affect drug metabolism, its impact on anti-TB drugs has not been thoroughly explored. This study sought to elucidate the relationship between pre-treatment gut microbiota and drug exposure levels among patients with pulmonary TB. Two cohorts were analyzed: a discovery cohort (N = 99) and a validation cohort (N = 32), both comprising patients undergoing anti-TB therapy with rifampicin, isoniazid, pyrazinamide, and ethambutol. The gut microbiota patterns of participants from the discovery cohort and the validation cohort were profiled by 16S rRNA gene sequencing and metagenomics, respectively. Analyses of both cohorts robustly established a positive association between pre-treatment microbial diversity and drug exposure, as well as significant differences in gut microbiota composition across various drug exposure groups. At the species level, Faecalibacterium prausnitzii was positively associated with drug exposure to rifampicin. Moreover, functional analysis revealed that starch and sucrose metabolism and secondary bile acid biosynthesis were more abundant in the high drug exposure group. To identify biomarkers capable of stratifying patients based on their drug exposure levels, 11 taxa, represented by Faecalibacterium, were selected in the discovery cohort (AUC = 0.992) and were confirmed in the validation cohort with high predictive accuracy (AUC = 0.894). This study demonstrated a correlation between microbial dysbiosis and reduced exposure to anti-TB medications. Optimizing treatment by regulating gut microbiota to improve drug exposure levels requires further validation through larger scale multicenter clinical trials.

The gut microbiome has a crucial role in cancer development and therapy through its interactions with the immune system and tumour microenvironment. Although evidence links gut microbiota composition to cancer progression, its precise role in modulating treatment responses remains unclear. In this Review, we summarize current knowledge on the gut microbiome's involvement in cancer, covering its role in tumour initiation and progression, interactions with chemotherapy, radiotherapy and targeted therapies, and its influence on cancer immunotherapy. We discuss the impact of microbial metabolites on immune responses, the relationship between specific bacterial species and treatment outcomes, and potential microbiota-based therapeutic strategies, including dietary interventions, probiotics and faecal microbiota transplantation. Understanding these complex microbiota-immune interactions is critical for optimizing cancer therapies. Future research should focus on defining microbial signatures associated with treatment success and developing targeted microbiome modulation strategies to enhance patient outcomes.

Recent evidence underscores a reciprocal relationship between the gut microbiota and prostate cancer (PCa). Dysbiosis, often driven by Western dietary habits and antibiotic use, can heighten systemic inflammation and hinder antitumor immunity, thereby fostering PCa onset and progression. Conversely, certain gut microbes and their metabolites may protect against tumor growth by modulating immune and hormonal pathways that impact therapeutic responses, including androgen deprivation therapy (ADT). Emerging evidence links gut microbial shifts to PCa aggressiveness, potentially sustaining local androgen production and promoting resistance. In this review, we explore current understanding of the gut-PCa interplay, highlighting key knowledge gaps and the need for further research to clarify how targeting the microbiome might influence PCa outcomes.

The gut microbiome influences the host immune system, cancer development and progression, as well as the response to immunotherapy during cancer treatment. Here, we analyse the composition of the gut bacteriome in metastatic Non-Small Cell Lung Cancer (NSCLC) patients receiving Pembrolizumab immunotherapy within a prospective maintenance trial through opportunistic sampling during treatment.

The gut microbiome profiles of NSCLC patients were obtained from stool samples collected during Pembrolizumab treatment and analysed with 16S rRNA metagenomics sequencing. Patient profiles were compared to a group of healthy individuals of matching ethnic group, age, sex, BMI and comorbidities.

A significant decrease in the treated patients was observed in two prominent bacterial families of the phylum Firmicutes, Lachnospiraceae and Ruminoccocaceae, which comprised 31.6% and 21.8% of the bacteriome in the healthy group but only 10.9% and 14.2% in the treated patient group, respectively. Species within the Lachnospiraceae and Ruminococcaceae families are known to break down undigested carbohydrates generating short chain fatty acids (SCFA), such as butyrate, acetate and propionate as their major fermentation end-products, which have been implicated in modifying host immune responses. In addition, a significant increase of the Bacteroidacaeae family (Bacteroidetes phylum) was observed from 10.7% in the healthy group to 23.3% in the treated patient group. Moreover, and in agreement with previous studies, a decrease in the Firmicutes to Bacteroidetes ratio in the metastatic NSCLC Pembrolizumab-treated patients was observed.

The observed differences indicate dysbiosis and a compromised intestinal health status in the metastatic NSCLC Pembrolizumab-treated patients. This data could inform future studies of immunotherapy treatment responses and modulation of the gut microbiome to minimise dysbiosis prior or concurrent to treatment.

SWIPE Trial (NCT02705820).

Head and neck cancers, including cancers of the mouth, throat, voice box, salivary glands, and nose, are a significant global health issue. Radiotherapy and surgery are commonly used treatments. However, due to treatment resistance and disease recurrence, new approaches such as immunotherapy are being explored. Immune checkpoint inhibitors (ICIs) have shown promise, but patient responses vary, necessitating predictive markers to guide appropriate treatment selection. This study investigates the potential of non-invasive biomarkers found in saliva, oral rinses, and tumor-derived exosomes to predict ICI response in head and neck cancer patients. The tumor microenvironment significantly impacts immunotherapy efficacy. Oral biomarkers can provide valuable information on composition, such as immune cell presence and checkpoint expression. Elevated tumor mutation load is also associated with heightened immunogenicity and ICI responsiveness. Furthermore, the oral microbiota may influence treatment outcomes. Current research aims to identify predictive salivary biomarkers. Initial studies indicate that tumor-derived exosomes and miRNAs present in saliva could identify immunosuppressive pathways and predict ICI response. While tissue-based markers like PD-L1 have limitations, combining multiple oral fluid biomarkers could create a robust panel to guide treatment decisions and advance personalized immunotherapy for head and neck cancer patients.

Black-bone silky fowl (Gallus gallus domesticus Brisson), medicinal food homology, utilizes to enhance human immunity. However, it remains unclear whether Black-bone silky fowl melanin (BSFM), one of its bioactive components, could affect immune function. The purpose of this study is to examine the immunoregulatory effect and the underlying mechanism of BSFM in the cyclophosphamide-induced immunosuppressive mice model. The findings revealed that BSFM could significantly increase white blood cells (WBC) in peripheral blood; upregulate the expression of IL-4, TNF-α, and M-CSF in the plasma; and reduce tissue damage. Mechanistically, proteomics has revealed that BSFM therapy substantially affected the quantity of 29 proteins (Mtatp6, Cst3, Pglyrp1, Igkc, and other targets), which mostly participate in the phosphatidylcholine catabolic process, positive regulation of type IIa hypersensitivity, lipid catabolic process, and neutrophil chemotaxis. Metabolomics indicated that BSFM reduced the levels of Octanoylglucuronide, Gly-Gly, and N-alpha-acetyl-ornithine and modulated arginine biosynthesis. Furthermore, BSFM treatment modified the composition of gut microbiota and increased the relative abundance of Prevotella, S24-7, Olsenella, Lactococcus, hgcl-clade, Parasutterella, and Acetobacter. A significant correlation modified the composition of gut microbiota among inflammation-associated parameters, gut microbiota, and various metabolites (DMs) through Pearson correlation analysis. These findings suggest that BSFM holds promise in enhancing the human immune system and may serve as a complementary therapy in conventional chemotherapy.

The human microbiome has always been an important determinant of health and recently, its role has also been described in cancer. The altered microbiome could aid cancer progression, modulate chemoresistance and significantly alter drug efficacy. The broad implications of microbes in cancer have prompted researchers to investigate the microbe-cancer axis and identify whether modifying the microbiome could sensitize cancer cells for therapy and improve the survival outcome of cancer patients. The preclinical data has shown that enhancing the number of specific microbial species could restore the patients' response to cancer drugs and the microbial biomarkers may play a vital role in cancer diagnostics. The elucidation of detailed interactions of the human microbiota with cancer would not only help identify the novel drug targets but would also enhance the efficacy of existing drugs. The field exploring the emerging roles of microbiome in cancer is at a nascent stage and an in-depth scientific perspective on this topic would make it more accessible to a wider audience. In this review, we discuss the scientific evidence connecting the human microbiome to the origin and progression of cancer. We also discuss the potential mechanisms by which microbiota affects initiation of cancer, metastasis and chemoresistance. We highlight the significance of the microbiome in therapeutic outcome and evaluate the potential of microbe-based cancer therapy.

The gut microbiome plays a crucial role in modulating the efficacy and toxicity of cancer therapies, particularly in hematological malignancies. This review examines the dynamic interplay between gut microbiota and cancer treatments, such as chemotherapy, immunotherapy, and hematopoietic stem cell transplantation (HSCT). Disruptions in the gut microbiome, known as dysbiosis, are associated with adverse effects like gastrointestinal toxicity, neutropenia and cardiotoxicity during chemotherapy. Conversely, the supplementation of probiotics has shown potential in mitigating these side effects by enhancing gut barrier function and regulating immune responses. In HSCT, a higher diversity of gut microbiota is linked to better patient outcomes, including reduced graft-versus-host disease (GVHD) and improved survival rates. The microbiome also influences the efficacy of immunotherapies, such as immune checkpoint inhibitors and CAR-T cell therapy, by modulating immune pathways. Research suggests that certain bacteria, including Bifidobacterium and Akkermansia muciniphila, enhance therapeutic responses by promoting immune activation. Given these findings, modulating the gut microbiome could represent a novel strategy for improving cancer treatment outcomes. The growing understanding of the microbiome's impact on cancer therapy underscores its potential as a target for personalized medicine and offers new opportunities to optimize treatment efficacy while minimizing toxic side effects.

The human microbiome plays a pivotal role in host health and disease, with emerging evidence underscoring its significant influence on the development and progression of breast cancer. Studies have revealed that dysbiosis in both the gut and breast tissue microbiota is strongly associated with an elevated risk of breast cancer. Distinct microbial profiles have been identified among healthy individuals, patients with benign breast conditions, and those with malignant tumors, with further variations observed across different ethnic groups and breast cancer subtypes. The complex interplay between breast cancer risk factors and microbial populations, coupled with the direct impact of microbial communities and their metabolites on inflammatory pathways and immune responses, underscores the importance of this field. Additionally, the interaction between gut microbiota and therapeutic modalities such as chemotherapy and radiotherapy is of particular interest, as these interactions can significantly influence treatment outcomes, either enhancing or diminishing efficacy. This review explores the effects of the Mediterranean diet, probiotics, prebiotics, and natural medicinal products on gut microbiota, emphasizing their potential as innovative therapeutic strategies. Notably, the use of engineered probiotics within the tumor microenvironment represents a promising frontier in breast cancer treatment. In conclusion, research on the human microbiome not only deepens our understanding of breast cancer pathogenesis but also lays the groundwork for the development of novel and targeted therapeutic interventions.

Despite the growing number of studies on the role of gut microbiota in treating gastrointestinal tumors, the overall research trends in this field remain inadequately characterized.

A bibliometric analysis was conducted using publications retrieved from the Web of Science Core Collection (up to September 30, 2024). Analytical tools including VOSviewer, CiteSpace, and an online bibliometric platform were employed to evaluate trends and hotspots.

Analysis of 1,421 publications revealed significant geographical disparities in research output, with China and the United States leading contributions. Institutionally, the University of Adelaide, Zhejiang University, and Shanghai Jiao Tong University were prominent contributors. Authorship analysis identified Hannah R. Wardill as the most prolific author, while the International Journal of Molecular Sciences emerged as a leading journal. Rapidly growing frontiers include "proliferation," "inhibition," "immunotherapy," "drug delivery," and "tumorigenesis."

This study provides a comprehensive overview of research trends and highlights emerging directions, aiming to advance scientific and clinical applications of gut microbiota in gastrointestinal tumor therapy.

The gut microbiome plays a pivotal role in modulating cancer therapies, including immunotherapy and chemotherapy. Emerging evidence demonstrates its influence on treatment efficacy, immune response, and resistance mechanisms. Specific microbial taxa enhance immune checkpoint inhibitor efficacy, while dysbiosis can contribute to adverse outcomes. Chemotherapy effectiveness is also influenced by microbiome composition, with engineered probiotics and prebiotics offering promising strategies to enhance drug delivery and reduce toxicity. Moreover, microbial metabolites, such as short-chain fatty acids, and engineered microbial systems have shown potential to improve therapeutic responses. These findings underscore the importance of personalized microbiome-based approaches in optimizing cancer treatments.

Background: The human microbiome plays a crucial role in health and disease. Dysbiosis, an imbalance of microorganisms, has been implicated in cancer development and treatment response, including in primary brain tumors and brain metastases, through interactions mediated by the gut-brain axis. This scoping review synthesizes current evidence on the relationship between the human microbiome and brain tumors. Methods: A systematic search of five electronic databases was conducted by an expert librarian, using controlled vocabulary and keywords. A targeted grey literature search in Google Scholar and clinical trial registries was also undertaken. Eligible studies included primary research involving human patients, or in vivo, or in vitro models of glioma or brain metastasis, with a focus on the microbiome's role in tumor development, treatment response, and outcomes. Results: Out of 584 citations screened, 40 studies met inclusion criteria, comprising 24 articles and 16 conference abstracts. These included 12 human studies, 16 using mouse models, 7 combining both, and 5 employing large datasets or next-generation sequencing of tumor samples. Thirty-one studies focused on primary brain tumors, six on brain metastases, and three on both. Of the 20 studies examining dysbiosis in tumor development, 95% (n = 19) found an association with tumor growth. Additionally, 71.4% (n = 5/7) of studies reported that microbiome alterations influenced treatment efficacy. Conclusions: Although the role of the gut-brain axis in brain tumors is still emerging and is characterized by heterogeneity across studies, existing evidence consistently supports a relationship between the gut microbiome and both brain tumor development and treatment outcomes.

Radiation therapy (RT) is a crucial modality in cancer treatment, functioning through direct DNA damage and immune stimulation. However, RT's effects extend beyond targeted cells, influencing neighboring cells through the bystander effect (ByE) and distant sites via the abscopal effect (AbE). The AbE, first described by Mole in 1953, encompasses biological reactions at sites distant from the irradiation field. While RT can enhance antitumor immune responses, it may also contribute to an immunosuppressive microenvironment. To address this limitation, combining RT with immune checkpoint inhibitors (ICIs) has gained renewed interest, aiming to amplify antitumor immune responses. Evidence of AbEs has been observed in various metastatic or advanced cutaneous cancers, including melanoma, basal cell carcinoma, cutaneous lymphoma, Merkel cell carcinoma, and cutaneous squamous cell carcinoma. Clinical studies suggest combining RT with ICIs targeting CTLA-4 and PD-1/PD-L1 may enhance AbE incidence in these cancers. This review primarily explores the current understanding of AbEs in skin cancers, briefly acknowledging the ByE focusing on combining RT with immunomodulation. It focuses on proposed mechanisms, preclinical and clinical evidence, challenges in clinical translation, and future directions for harnessing AbEs in managing advanced skin malignancies. Alternative modalities for inducing abscopal-like responses are also explored. While promising, challenges remain in consistently reproducing AbEs in clinical practice, necessitating further research to optimize treatment combinations, timing, and patient selection.

Inulin consumption and dihydrogen (H2) administration both exert antitumor effects on preclinical models as well as in clinical trials. As H2 is one of the major byproducts of inulin fermentation by bacterial species of the gut microbiota (GM), we hypothesized that H2 could mediate the antitumor effects of inulin. To provide evidence in favor of this hypothesis, we first determined the pattern of H2-exposure to which mice are subjected after inulin administration and developed an inhaled hydrogen therapy (H2T) protocol replicating this pattern. We then compared the effects on circulating immunity of a two-week daily inulin gavage with those of the corresponding H2T. We also compared the effects of inulin supplementation to those of the corresponding H2T on implanted melanoma growth and infiltration by T lymphocytes. Inulin and H2T induced a similar increase in circulating CD4+ and CD8+ T cells. In addition, both treatments similarly inhibited melanoma tumor growth. These results support a mechanism by which the H2 resulting from inulin fermentation by the GM diffuses across the intestinal barrier and stimulates the immunosurveillance responsible for the antitumor effect.

In recent years, evidence has shown that the gut microbiome significantly influences responses to immunotherapy. This has sparked interest in targeting it to improve therapy outcomes and predictions of response and toxicity. Research has demonstrated that dysbiosis, often resulting from antibiotic use, can diminish the effectiveness of immune checkpoint inhibitors, and this lack of efficacy could be linked to systemic inflammation. Certain bacterial species have been identified as having beneficial and harmful effects on immunotherapy in the clinic. While a clear consensus has yet to emerge on the optimal species for therapeutic use, introducing a new microbiome into immunotherapy-refractory patients may boost their chances of responding to further treatment attempts. State-of-the-art interventions targeting the microbiome-such as fecal microbiota transplantation-are being assessed clinically for their safety and potential to enhance treatment outcomes, with promising results. Additionally, the microbiome has been leveraged for its power to predict clinical outcomes using machine learning, and surprisingly, its predictive capability is comparable to that of other described multi-biomarker clinical scores. Here, we discuss developing knowledge concerning the microbiome's significance in cancer immunotherapy and outline future strategies for maximizing its potential in immuno-oncology.

Standard clinical parameters like tumor size, age, lymph node status, and molecular markers are used to predict progression risk and treatment response. However, exploring additional markers that reflect underlying biology could offer a more comprehensive understanding of the tumor microenvironment (TME). The TME influences tumor development, progression, disease severity, and survival, with tumor-associated bacteria posited to play significant roles. Studies on tumor-associated microbiota have focused on high bacterial-load sites such as the gut, oral cavity, and stomach, but interest is growing in non-gastrointestinal (GI) solid tumors, such as breast, lung, and pancreas. Microbe-based biomarkers, including Helicobacter pylori, human papillomavirus (HPV), and hepatitis B and C viruses, have proven valuable in predicting gastric, cervical, and renal cancers.

Potential of prognostic and predictive bacterial biomarkers in non-GI solid tumors and the methodologies used.

Advances in techniques like 16S rRNA gene sequencing, qPCR, immunostaining, and in situ hybridization have enabled detailed analysis of difficult-to-culture microbes in solid tumors. However, to ensure reliable results, it is critical to standardize protocols, accurately align reads, address contamination, and maintain proper sample handling. This will pave the way for developing reliable bacterial markers that enhance prognosis, prediction, and personalized treatment planning.

Bladder cancer (BCa) remains a significant source of morbidity and mortality. BCa is one of the most expensive tumors to treat, in part because of a lack of nonsurgical options. The recent advent of immunotherapy, alone or in combination with other compounds, has improved therapeutic options. Resistance to immunotherapy remains common, and many patients do not have durable response. Recent advances indicate immunotherapy efficacy may be tied in part to the endogenous bacteria present in our body, more commonly referred to as the microbiome. Laboratory and clinical data now support the idea that a healthy microbiome is critical to effective response to immunotherapy. At the same time, pathogenic interactions between the microbiome and immune cells can also serve to drive formation of tumors, increasing the complexity of these interactions. Given the rising importance of immunotherapy in BCa, understanding how we might be able to alter the microbiome to improve therapeutic efficacy offers a novel route to improved patient care. The goal of this review is to examine our current understanding of microbial interactions with the immune system and cancer with an emphasis on BCa. We will further attempt to define both current gaps in knowledge and future directions that may yield beneficial results to the field.

The European Union-sponsored ONCOBIOME network has spurred an international effort to identify and validate relevant gut microbiota-related biomarkers in oncology, generating a unique and publicly available microbiome resource. ONCOBIOME explores the effects of the microbiota on gut permeability and metabolism as well as on antimicrobial and antitumor immune responses. Methods for the diagnosis of gut dysbiosis have been developed based on oncomicrobiome signatures associated with the diagnosis, prognosis and treatment responses in patients with cancer. The mechanisms explaining how dysbiosis compromises natural or therapy-induced immunosurveillance have been explored. Through its integrative approach of leveraging multiple cohorts across populations, cancer types and stages, ONCOBIOME has laid the theoretical and practical foundations for the recognition of microbiota alterations as a hallmark of cancer. ONCOBIOME has launched microbiota-centered interventions and lobbies in favor of official guidelines for avoiding diet-induced or iatrogenic (for example, antibiotic- or proton pump inhibitor-induced) dysbiosis. Here, we review the key advances of the ONCOBIOME network and discuss the progress toward translating these into oncology clinical practice.

Immunotherapy has achieved remarkable advances in cancer treatment by harnessing the immune system to combat tumors, yet its effectiveness remains inconsistent across patients and tumor types. The microbiota, a diverse assemblage of microorganisms residing at host barrier surfaces, is pivotal in shaping immune responses. This review explores the direct and indirect mechanisms via which the microbiota modulates antitumor immune responses both locally within the tumor microenvironment and systemically by affecting distant tumors. We discuss recent findings linking microbiota-derived metabolites and microbiota-derived antigens with antitumor immunity and immunotherapy response. Additionally, we discuss recent advances in microbiome-based therapies, including fecal microbiota transplantation. We propose the use and development of new analytical techniques to further characterize the complex functions and interactions between the microbiome and immune system. To conclude, we outline recommendations for future research and therapeutic approaches to leverage the microbiome to improve current immunotherapies.

Growing evidence suggests that cancer should not be viewed solely as a genetic disease but also as the result of functional defects in the metaorganism, including disturbances in the gut microbiota (i.e., gut dysbiosis). The human microbiota plays a critical role in regulating epithelial barrier function in the gut, airways, and skin, along with host metabolism and systemic immune responses against microbes and cancer. Collaborative international networks, such as ONCOBIOME, are essential in advancing research equity and building microbiome resources to identify and validate microbiota-related biomarkers and therapies. In this review, we explore the intricate relationship between the microbiome, metabolism, and cancer immunity, and we propose microbiota-based strategies to improve outcomes for individuals at risk of developing cancer or living with the disease.

The human microbiome, an intricate ecosystem of trillions of microbes residing across various body sites, significantly influences cancer, a leading cause of morbidity and mortality worldwide. Recent studies have illuminated the microbiome's pivotal role in cancer development, either through direct cellular interactions or by secreting bioactive compounds such as metabolites. Microbial metabolites contribute to cancer initiation through mechanisms such as DNA damage, epithelial barrier dysfunction, and chronic inflammation. Furthermore, microbial metabolites exert dual roles on cancer progression and response to therapy by modulating cellular metabolism, gene expression, and signaling pathways. Understanding these complex interactions is vital for devising new therapeutic strategies. This review highlights microbial metabolites as promising targets for cancer prevention and treatment, emphasizing their impact on therapy responses and underscoring the need for further research into their roles in metastasis and therapy resistance.

Vaginal atrophy is a prevalent symptom in menopausal women, affecting over 50% of older women and patients with loss of ovarian function. The role of factors other than estrogen, such as the vaginal microbiota (VM), in the development of vaginal atrophy has not been fully explored. Therefore, we selected 8-week-old C57 mice with bilateral ovariectomy for experimentation. After four weeks of treatment, we observed that the vaginal epithelium of ovariectomized mice showed signs of atrophy. There were also significant differences in the structure and metabolites of VM. Vaginal transplantation of microbiota from ovary-intact mice significantly alleviated the vaginal atrophy of ovariectomized mice and altered the structure and metabolism of VM. These findings indicate that ovarian activity significantly affects the structure and metabolism of VM. VM of ovary-intact mice may promote vaginal health by upregulating the estrogen receptor alpha gene (ESR1, one-way ANOVA, F4, 25 = 17.76, P < 0.0001) in vaginal epithelial cells in ovariectomized mice, which in turn promotes cell proliferation (the number of vaginal epithelial cell layers, one-way ANOVA, F4, 25 = 28.04, P < 0.0001). Further studies are needed to investigate the interactions between VM and vaginal health. This finding can help develop new therapeutic strategies and interventions for patients suffering from vaginal atrophy.

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.

Elevated levels of the NAD+-generating enzyme nicotinamide phosphoribosyltransferase (NAMPT) are a common feature across numerous cancer types. Accordingly, we previously reported pervasive NAD+ dysregulation in multiple myeloma (MM) cells in association with upregulated NAMPT expression. Unfortunately, albeit being effective in preclinical models of cancer, NAMPT inhibition has proven ineffective in clinical trials because of the existence of alternative NAD+ production routes using NAD+ precursors other than nicotinamide. Here, by leveraging mathematical modeling approaches integrated with transcriptome data, we defined the specific NAD+ landscape of MM cells and established that the Preiss-Handler pathway for NAD+ biosynthesis, which uses nicotinic acid as a precursor, supports NAD+ synthesis in MM cells via its key enzyme nicotinate phosphoribosyltransferase (NAPRT). Accordingly, we found that NAPRT confers resistance to NAD+-depleting agents. Transcriptomic, metabolic, and bioenergetic profiling of NAPRT-knockout (KO) MM cells showed these to have weakened endogenous antioxidant defenses, increased propensity to oxidative stress, and enhanced genomic instability. Concomitant NAMPT inhibition further compounded the effects of NAPRT-KO, effectively sensitizing MM cells to the chemotherapeutic drug, melphalan; NAPRT added-back fully rescues these phenotypes. Overall, our results propose comprehensive NAD+ biosynthesis inhibition, through simultaneously targeting NAMPT and NAPRT, as a promising strategy to be tested in randomized clinical trials involving transplant-eligible patients with MM, especially those with more aggressive disease.

Microecology refers to the ecosystem formed by human and microbial communities in the process of co-evolution, the microecological imbalance is associated with occurrence and development of multiple diseases, including lung cancer. In this review, we detailedly summarized the concept and roles of microecology, the relationship between microecology and human diseases, and related techniques in microecology studies. Importantly, we specially analyzed the correlations between microecology and lung cancer by focusing on gut microbiota, oral microbiota and lower respiratory tract microbiota, and further evaluated the effects of microbiota dysbiosis on chemotherapy and immunotherapy efficacy in lung cancer. At last, we discussed the potential mechanisms by which dysregulated microbiota promotes the genesis and development of lung cancer. Microecology-centered detection and intervention will improve the early diagnosis of lung cancer and provide new targets for the treatment of lung cancer.

To investigate the gut microbiome of lung cancer patients with brain metastases undergoing radiotherapy, identify key microorganisms associated with radiotherapy response, and evaluate their potential as biomarkers.

This study enrolled 55 newly diagnosed lung cancer patients with brain metastases. Fecal samples were collected before radiotherapy and analyzed by 16S rRNA sequencing to assess the gut microbiome's composition and function. Patients were categorized into response (n=28) and non-response (n=27) groups based on treatment efficacy, and α-diversity, β-diversity, and functional pathways were compared between them. Linear Discriminant Analysis Effect Size was used to identify microbial features associated with treatment efficacy. Logistic regression analyses were performed to evaluate the predictive capacity of clinical and microbial factors for treatment outcomes.

No significant difference in α-diversity was observed between the groups (P > 0.05), but β-diversity differed significantly (P = 0.036). Twelve characteristic microorganisms were identified in the response group, including g_ Oscillibacter and g_ Blautia, and nine in the non-response group, such as f_ Desulfovibrionaceae and g_ Megamonas. Metabolic pathways associated with treatment response included ketone body metabolism and pathways related to amyotrophic lateral sclerosis. Multivariate analysis identified g_Flavonifractor (odds ratio [OR] = 6.680, P = 0.004), g_Negativibacillus (OR = 3.862, P = 0.014), C-reactive protein (OR = 1.054, P = 0.017), and systemic inflammation response index (OR = 1.367, P = 0.043) as independent predictors of radiotherapy response. The nomogram and microbiome models achieved area under the curve (AUC) values of 0.935 and 0.866, respectively, demonstrating excellent predictive performance. Decision curve analysis further confirmed these models provided significant net benefits across risk thresholds.

The composition and functional characteristics of the gut microbiome in lung cancer patients with brain metastases prior to radiotherapy are associated with therapeutic response and possess potential as predictive biomarkers. Further studies are warranted to validate these findings.

Anti-tumor immunity, including innate and adaptive immunity is critical in inhibiting tumorigenesis and development of tumor. The adaptive immunity needs specific lymph organs such as tertiary lymphoid structures (TLSs), which are highly correlated with improved survival outcomes in many cancers. In recent years, with increasing attention on the TLS in tumor microenvironment, TLSs have emerged as a novel target for anti-tumor therapy. Excitingly, studies have shown the contribution of TLSs to the adaptive immune responses. However, it is unclear how TLSs to form and how to more effectively defense against tumor through TLS formation. Recent studies have shown that the inflammation plays a critical role in TLS formation. Interestingly, studies have also found that gut microbiota can regulate the occurrence and development of inflammation. Therefore, we here summarize the potential effects of gut microbiota- mediated inflammation or immunosuppression on the TLS formation in tumor environments. Meanwhile, this review also explores how to manipulate mature TLS formation through regulating gut microbiota/metabolites or gut microbiota associated signal pathways for anti-tumor immunity, which potentially lead to a next-generation cancer immunotherapy.

"Chemobrain" refers to the cognitive impairment induced by chemotherapy. The doxorubicin and cyclophosphamide cocktail has been used for various cancers, especially breast cancer. However, both have been linked to chemobrain as well as gastrointestinal toxicity. Despite being distinct organs, the gut and the brain have a bidirectional connection between them known as the gut-brain axis. This research aimed to study the neuroprotective effect of troxerutin, a rutin derivative, in chemobrain induced by doxorubicin and cyclophosphamide via a potential impact on the gut-inflammasome-brain axis. Troxerutin was administered at 75, 150, and 300 mg/kg doses. Furthermore, behavioral, histological, and acetylcholinesterase assessments were performed. Accordingly, the highest dose of troxerutin was selected to investigate the potential underlying mechanisms. Troxerutin treatment reversed the chemotherapy-fecal metabolite alterations. Additionally, troxerutin demonstrated positive effects against deterioration of intestinal integrity, permeability, and microbial endotoxins translocation, as evidenced by its effect on tight junction proteins; ZO-1, and claudin-1 expression, and lipopolysaccharide serum levels. Consequently, troxerutin hindered lipopolysaccharide-induced oxidative damage, systemic inflammation, and neuroinflammation. Moreover, troxerutin demonstrated antioxidant effects via its impact on lipid peroxidation, catalase levels, and the Nrf2/HO-1 pathway. Furthermore, chemotherapy-induced inflammation was opposed by troxerutin via downregulation of NLRP3, caspase-1, and the downstream cytokines; IL-18 and IL-1β. Importantly, troxerutin did not abrogate the anticancer activity of doxorubicin and cyclophosphamide in human MCF7 cells. Collectively, our study suggested the potentiality of troxerutin as a therapeutic choice against chemobrain by inhibiting the gut-inflammasome-brain axis and hindering acetylcholinesterase, oxidative stress, and neuroinflammation.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma with over 5000 new patients diagnosed in the USA each year. The tumor originates from the interstitial cells of Cajal and forms an intramural lesion most commonly in the stomach or small intestine. The gut microbiome has been linked to other gastrointestinal cancers and a recent paper purported that GISTs contain substantial intratumoral bacteria. The purpose of this study is to further evaluate the presence of bacteria in GISTs.

We collected 25 tumor samples of varying size and location from 24 patients under sterile conditions in the operating room immediately following surgical resection. 16S quantitative polymerase chain reaction (qPCR) and 16S ribosomal RNA (rRNA) gene amplicon sequencing were performed to evaluate the bacterial species present in each tumor. Retrospective chart review was performed to determine tumor characteristics, including tumor size, location, imatinib exposure, and mucosal involvement.

In 23 of the 25 tumor samples, there were fewer than 100 copy numbers of 16S rRNA per uL, indicating an absence of a significant bacterial load. 16S rRNA gene amplicon sequencing of the remaining two samples, one gastric tumor and one duodenal tumor, revealed the presence of normal intestinal bacteria. These two tumors, along with three others, had disruption of the mucosal lining.

GISTs generally lack substantial bacteria, except in some cases when the tumor disrupts the mucosa.

The skin microbiome plays a crucial role in maintaining skin health, defending the body against harmful pathogens, and interacting with melanoma. The composition of the skin microbiome can be affected by factors like age, gender, ethnicity, lifestyle, diet, and UV exposure. Certain bacteria like Staphylococcus and Veillonella are important for wound healing, while Cutibacterium acnes can play a role in dermatoses. UV radiation alters the skin microbiome, originates a "UV-resistome" and can lead to skin cancer initiation. Specifically, Staphylococcus epidermidis has shown protective effects against skin cancer, whereas Cutibacterium acnes can induce apoptosis in melanocytes postirradiation. The microbiome also interacts with melanoma treatment, affecting responses to immune checkpoint inhibitors. Strategies like bacteriotherapy, involving the manipulation of the gut microbiome but also the skin microbiome (with the gut-skin axis or through topical treatment) could improve treatment outcomes and show promise in melanoma therapy. Understanding the complex interplay between the skin microbiome, UV exposure, and melanoma development is crucial for developing personalized therapeutic approaches. Investigation into the skin microbiome and its potential role in melanoma progression continues to be an exciting area of research with implications for future therapeutic interventions.

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.

Antibiotic (ABX)-induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T-cell (CAR-T) therapies. In this study, we observed that prior exposure to broad-spectrum ABXs with extended anaerobic coverage such as piperacillin-tazobactam and meropenem was associated with worse anti-CD19 CAR-T therapy survival outcomes in patients with large B-cell lymphoma (N = 422) than other ABX classes. In a discovery subset of these patients (n = 67), we found that the use of these ABXs was in turn associated with substantial dysbiosis of gut microbiome function, resulting in significant alterations of the gut and blood metabolome, including microbial effectors such as short-chain fatty acids (SCFAs) and other anionic metabolites, findings that were largely reproduced in an external validation cohort (n = 58). Broader evaluation of circulating microbial metabolites revealed reductions in indole and cresol derivatives, as well as trimethylamine N-oxide, in patients who received ABX treatment (discovery, n = 40; validation, n = 28). These findings were recapitulated in an immune-competent CAR-T mouse model, in which meropenem-induced dysbiosis led to a systemic dysmetabolome and decreased murine anti-CD19 CAR-T efficacy. Furthermore, we demonstrate that SCFAs can enhance the metabolic fitness of CAR-Ts, leading to improved tumor killing capacity. Together, these results suggest that broad-spectrum ABX deplete metabolically active commensals whose metabolites are essential for enhancing CAR-T efficacy, shedding light on the intricate relationship between ABX exposure, microbiome function and their impact on CAR-T efficacy. This highlights the potential for modulating the microbiome to augment CAR-T immunotherapy. This trial was registered at www.clinicaltrials.gov as #NCT06218602.

This study evaluated the role of probiotics in enhancing intestinal immunity and mitigating polystyrene nanoplastics (PS-NPs)-induced toxicity in grass carp (Ctenopharyngodon idella). Grass carp were fed probiotics (Bacillus subtilis, Bacillus velezensis, Lactobacillus reuteri, and Lactococcus lactis) for two weeks before being exposed to PS-NPs for five days. Probiotic pretreatment alleviated PS-NPs-induced intestinal damage, with Bacillus velezensis and Lactococcus lactis groups showing milder vacuolation and villus breakage than other groups. Probiotic-treated fish exhibited transient increases in antioxidant enzyme activities (CAT, SOD, MPO) and immune gene expression (IL-6, IL-8, IL-10, IL-1β, TNF-α, and IFN-γ2) shortly after exposure, followed by significant downregulation over time. Higher abundance of the gut dominant phylum Proteobacteria was observed in four probiotic groups exposed to PS-NPs than that in the blank control group. The Clostridium phylum showed a significant decrease in the abundance both in the LRS-PS100 and LLS-PS100 groups, while the abundance of the Thick-walled phylum increased. The Spearman correlation matrix revealed that specific gut microbiota, such as Serratia, Neisseria, and Lactococcus, were significantly associated with enzymatic activities and immune system related genes' expressions. Probiotic pretreatment enhanced the intestinal immune response of grass carp. However, this enhanced immune response was insufficient to counteract the toxic effects of PS-NPs exposure, particularly in terms of oxidative stress levels and gut microbial diversity. This study offers new insights into the potential of probiotics to combat NPs pollution in aquaculture. It emphasizes the need for further research to explore various probiotic combinations. Future studies should also investigate optimal dosages and durations to effectively mitigate the biological toxicity of NPs pollution.