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.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with limited treatment options at advanced stages. The gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, plays a pivotal role in regulating immune responses through the gut-liver axis. Emerging evidence underscores its impact on HCC progression and the efficacy of immunotherapy. This review explores the intricate interactions between gut microbiota and the immune system in HCC, with a focus on key immune cells and pathways involved in tumor immunity. Additionally, it highlights strategies for modulating the gut microbiota - such as fecal microbiota transplantation, dietary interventions, and probiotics - as potential approaches to enhancing immunotherapy outcomes. A deeper understanding of these mechanisms could pave the way for novel therapeutic strategies aimed at improving patient prognosis.

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 antibiotic salinomycin, a well-known cancer stem cell inhibitor, may impact the diversity of the intestinal microbiota in colorectal cancer (CRC) mice, which plays a pivotal role in shaping the immune system. This study explores the anti-cancer effects and mechanisms of combining salinomycin and fecal microbiota transplantation (FMT) in treating CRC.

FMT was given via enema, while salinomycin was injected intraperitoneally into the CRC mouse model induced by azoxymethane/dextran sodium sulfate.

In CRC mice, a large number of LGR5-labeled cancer stem cells and severe disturbances in the intestinal microbiota were observed. Interestingly, salinomycin inhibited the proliferation of cancer stem cells without exacerbating the microbial disorder as expected. In comparison to salinomycin treatment, the combination of salinomycin and FMT significantly improved pathological damage and restored intestinal microbial diversity, which is responsible for shaping the anti-cancer immune microenvironment. The supplementation of FMT significantly increased the levels of propionic acid and butyric acid while also promoting the infiltration of CD8+ T cells and Ly6G+ neutrophils, as well as reducing F4/80+ macrophage recruitment. Notably, cytokines that were not impacted by salinomycin exhibited robust reactions to alterations in the gut microbiota. These included pro-inflammatory factors (IL6, IL12b, IL17, and IL22), chemokine-like protein OPN, and immunosuppressive factor PD-L1.

Salinomycin plays the role of "eliminating pathogenic qi," targeting cancer stem cells; FMT plays the role of "strengthening vital qi," reversing the intestinal microbiota disorder and enhancing anti-cancer immunity. They have a synergistic effect on the development of CRC.

The evidence suggests that the microbiome plays a crucial role in cancer development. The oral cavity has many microorganisms that can influence oral cancer progression. Understanding the mechanisms and signaling pathways of the oral, gum, and teeth microbiome in tumor progression can lead to new treatment strategies. Probiotics, which are friendly microorganisms, have shown potential as anti-cancer agents. These positive characteristics of probiotic strains make them suitable for cancer prevention or treatment. The oral-gut microbiome axis supports health and homeostasis, and imbalances in the oral microbiome can disrupt immune signaling pathways, epithelial barriers, cell cycles, apoptosis, genomic stability, angiogenesis, and metabolic processes. Changes in the oral microbiome in oral cancer may suggest using probiotics-based treatments for their direct or indirect positive roles in cancer development, progression, and metastasis, specifically oral squamous cell carcinoma (OSCC). Here, reported relationships between probiotics, oral microbiota, and oral cancer are summarized.

The integration of microbiome research and nanotechnology represents a significant advancement in immuno-oncology, potentially improving the effectiveness of cancer immunotherapies. Recent studies highlight the influential role of the human microbiome in modulating immune responses, presenting new opportunities to enhance immune checkpoint inhibitors (ICIs) and other cancer therapies. Nanotechnology offers precise drug delivery and immune modulation capabilities, minimizing off-target effects while maximizing therapeutic outcomes. This review consolidates current knowledge on the interactions between the microbiome and the immune system, emphasizing the microbiome's impact on ICIs, and explores the incorporation of nanotechnology in cancer treatment strategies. Additionally, it provides a forward-looking perspective on the synergistic potential of microbiome modulation and nanotechnology to overcome existing challenges in immuno-oncology. This integrated approach may enhance the personalization and effectiveness of next-generation cancer treatments, paving the way for transformative patient care.

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

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.

Identifying host genetic factors modulating immune checkpoint inhibitor (ICI) efficacy is experimentally challenging. Our approach, utilizing the Collaborative Cross mouse genetic resource, fixes the tumor genomic configuration while varying host genetics. We find that response to anti-PD-1 (aPD1) immunotherapy is significantly heritable in four distinct murine tumor models (H2: 0.18-0.40). For the MC38 colorectal carcinoma system, we map four significant ICI response quantitative trait loci (QTLs) with significant epistatic interactions. The differentially expressed genes within these QTLs that define responder genetics are highly enriched for processes involving antigen processing and presentation, allograft rejection, and graft vs. host disease (all p < 1 × 10-10). Functional blockade of two top candidate immune targets, GM-CSF and IL-2RB, completely abrogates the MC38 transcriptional response to aPD1 therapy. Thus, our in vivo experimental platform is a powerful approach for discovery of host genetic factors that establish the tumor immune microenvironment propitious for ICI response.

Colorectal cancer (CRC), as a high-incidence malignancy, continues to present significant challenges in prevention, screening, and treatment. Curcumin (Cur) exhibits notable anti-inflammatory and anticancer properties. Despite its poor solubility in water and low bioavailability, high concentrations of Cur are detected in the gastrointestinal tract after oral administration, suggesting that it may directly interact with the gut microbiota and exert regulatory effects. This study aims to explore the mechanisms by which Cur improves CRC by modulating gut microbiota. Firstly, we evaluated the effect of Cur on CRC cell viability in vitro using the MTT assay, and the results showed a significant inhibitory effect on CRC cell growth. The IC50 values for Cur in CT26 and RKO cells were 23.52 μM, 16.11 μM, and 13.62 μM at 24, 48, and 72 hours, respectively, and 26.3 μM, 16.52 μM, and 14.22 μM at 24, 48, and 72 hours, respectively. Cur induced apoptosis and caused G2 phase cell cycle arrest in tumor cells. Subsequently, we established a CRC mouse model. Oral administration of Cur at 15 mg kg-1 and 30 mg kg-1 inhibited CRC progression, as evidenced by reduced tumor volume, histological analysis, immunohistochemistry, and an increased number of CD8+ T cells infiltrating the tumors. Ferroptosis in tumor cells was also observed. Cur partially restored the gut microbiota of CRC mice, altering the abundance and diversity of the gut microbiota and affecting serum metabolite distribution, with significant increases in the abundance of SCFA-producing microbes such as Lactobacillus and Kineothrix. To verify causality, we designed a fecal microbiota transplantation (FMT) experiment. Compared with CRC mice, the fecal microbiota from Cur-treated mice significantly alleviated CRC symptoms, including slowed tumor growth, enhanced CD8+ T cell tumor infiltration, and induced ferroptosis in tumor cells. Additionally, when gut microbiota was depleted with antibiotics, Cur's antitumor effects disappeared, suggesting that Cur mitigates CRC in a gut microbiota-dependent manner. These findings provide new insights into the mechanisms underlying CRC and propose novel therapeutic interventions, emphasizing the interaction between gut microbiota and immune responses within the tumor immune microenvironment (TIME).

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.

In the tumor host, neutrophils may exhibit protumor or antitumor activity. It is hypothesized that in response to host-derived or therapy-induced factors, neutrophils adopt diverse functional states to ultimately execute these differential functions. Here, we provide an alternative scenario in which the response of an individual tumor cell population determines the overall protumor versus antitumor outcome of neutrophil‒tumor interactions. Experimentally, we show that human neutrophils, which are sequentially stimulated with bacteria and secreted factors from tumor cells, kill a certain proportion of tumor target cells. However, the majority of the tumor cells remained resistant to this neutrophil-mediated killing and underwent a functional, phenotypic and transcriptomic switch that was reminiscent of partial epithelial‒to-mesenchymal transition. This cell biological switch was associated with physical escape from NK-mediated killing and resulted in enhanced metastasis to the lymph nodes in a preclinical orthotopic mouse model. Mechanistically, we identified the antimicrobial neutrophil granule proteins neutrophil elastase (NE) and matrix metalloprotease-9 (MMP-9) as the molecular mediators of this functional switch. We validated these data in patients with head and neck cancer and identified bacterially colonized intratumoral niches that were enriched for mesenchymal tumor cells and neutrophils expressing NE and MMP-9. Our data reveal the parallel execution of tumor cytotoxic and prometastatic activity by activated neutrophils and identify NE and MMP-9 as mediators of lymph node metastasis. The identified mechanism explains the functional dichotomy of tumor-associated neutrophils at the level of the tumor target cell response and has implications for superinfected cancers and the dysbiotic tumor microenvironment.

Sjögren's syndrome (SS) is a complicated autoimmune disorder, encompassing multifaceted pathogenesis of inflammatory response, immune dysregulation and metabolic abnormalities. Shaoteng Decoction (STD) is a type of traditional Chinese medicine preparation that has been shown to effectively improve inflammatory damage and immune dysfunction in patients with SS. Nevertheless, the exact mechanism has not been unspecified.

This work aims to determine the mechanism of STD treatment on SS, identifying potential therapeutic targets and their relationships.

Non-obese diabetic mice served as a disease model. This study analyzes potential signaling pathways of STD treatment for SS through network pharmacology, and assesses the role of STD in reducing inflammatory damage using pathological staining, ELISA, and immunohistochemistry. Additionally, the study apply gut microbiota, metabolomics, and proteomics analyses to identify the key microbiota, metabolites and proteins, aiming to find potential action targets of STD. We use Western blotting and immunohistochemistry to verify the authenticity of the relevant targets and study the interactions among gut microbiota, metabolites, and proteins.

Proteobacteria is the important intestinal bacteria, Bile Acid Biosynthesis is the main metabolic pathway, IfI30, Ndufv3, and Ndufs6 are the crucial differential expressed proteins. Moreover, there is a strong correlation among the three. STD treats SS by reducing the abundance of Proteobacteria, increasing Bile Acid Biosynthesis, decreasing IfI30 expression, and increasing the expression of Ndufv3 and Ndufs6.

STD inhibits inflammatory responses, improves immune dysregulation and energy metabolism abnormalities, and prevents the progression of SS through regulating the gut microbiota, enhancing Bile Acid Biosynthesis, and modulating proteins expression levels.

BackgroundProbiotics, as common regulators of the gut microbiota, have been used in research to alleviate clinical symptoms of atopic dermatitis (AD).ObjectiveOur research team has previously identified a potential relieving effect of Clostridium butyricum on the treatment of AD, but the specific mechanism of how Clostridium butyricum alleviates AD has not yet been confirmed.MethodsIn this study, we explored the relieving effect of Clostridium butyricum on AD through in vivo and in vitro experiments. AD mice induced by 2,4-dinitrofluorobenzene (DNFB) were orally administered with 1 × 108 CFU of Clostridium butyricum for three consecutive weeks.ResultsOral administration of Clostridium butyricum reduced ear swelling, alleviated back skin lesions, decreased mast cell and inflammatory cell infiltration, and regulated the levels of inflammation-related cytokines. Clostridium butyricum activated the intestinal immune system through the TLR4/MyD88/NF-κB signaling pathway, suppressed the expression of inflammatory factors IL-10 and IL-13, and protected the damaged intestinal mucosa.ConclusionClostridium butyricum administration improved the diversity and abundance of the gut microbiota, enhanced the functionality of the immune system, and protected the epidermal barrier.

Adenosine diphosphate-ribosylation (ADPRylation) is a reversible posttranslational modification that plays a crucial role in cellular homeostasis and disease development. ADPRylation is produced via nicotinamide adenine dinucleotide hydrolysis and modifies proteins via corresponding transferases, mainly poly(ADP-ribose) polymerases (PARPs), the inhibitors of which have been used in the clinical treatment of cancer. ADPRylation is involved in various physiological processes, including pathogen infection, inflammation, DNA repair, and neurological disorders. In neurodegenerative diseases (NDs), dysregulated ADPRylation contributes to protein aggregation, neuroinflammation, and metabolic disturbances, while targeted modulation shows therapeutic potential. ADPRylation differentially regulates neurodegenerative processes, and PARP inhibitors can reduce neuroinflammation, oxidative stress, and metabolic dysfunction. However, challenges such as poor blood-brain barrier penetration and cell type-specific responses limit clinical translation. This review summarizes recent findings on the role of ADPRylation and PARPs in NDs, highlighting their involvement in protein aggregation and cellular signaling. It emphasizes the importance of ADPRylation in neuronal cells and supports the development of precision therapies targeting this pathway to address current treatment challenges in NDs.

The gut microbiota is a diverse ecosystem that significantly impacts human health and disease. This article focuses on how the gut microbiota interacts with inflammatory bowel diseases and colorectal tumors, especially through immune regulation. The gut microbiota plays a role in immune system development and regulation, while the body's immune status can also affect the composition of the microbiota. These microorganisms exert pathogenic effects or correct disease states in gastrointestinal diseases through the actions of toxins and secretions, inhibition of immune responses, DNA damage, regulation of gene expression, and protein synthesis. The microbiota and its metabolites are essential in the development and progression of inflammatory bowel diseases and colorectal tumors. The complexity and bidirectionality of this connection with tumors and inflammation might render it a new therapeutic target. Hence, we explore therapeutic strategies for the gut microbiota, highlighting the potential of probiotics and fecal microbiota transplantation to restore or adjust the microbial community. Additionally, we address the challenges and future research directions in this area concerning inflammatory bowel diseases and colorectal tumors.

We undertook this study to assess the efficacy of probiotics in managing adverse reactions during chemoradiotherapy in patients with colorectal cancer.

A comprehensive literature search was conducted on PubMed, ClinicalTrials.gov, Embase, Cochrane library,Web of Science, and Chinese databases until July 27, 2024. Data analysis was performed using RevMan5.3 statistical software. The risk of bias was assessed using the Cochrane collaboration tool. Relative risk (RR) was employed to incorporate statistical measures and calculate 95% confidence intervals (95%CI) for bipartite data. Standardized mean difference (SMD) was utilized to incorporate statistical measures and calculate 95% confidence intervals for continuous variables.

A meta-analysis of 633 patients with colorectal cancer was conducted across eight studies. In comparison to the control group, probiotics demonstrated a significant reduction in the incidence of chemoradiotherapy-induced diarrhea among colorectal cancer patients(RR = 0.51,95%Cl:0.38 ~ 0.68,P < 0.001). Additionally, probiotic usage exhibited improvements in pain index (SMD = -2.27,95%Cl: -4.49 ~ -0.05,P = 0.04), dyspnea (SMD = -0.92,95%Cl: -1.61 ~ 0.22, P = 0.01) and insomnia (SMD = -2.95, 95%Cl: -5.44 ~ -0.47, P = 0.02) compared to the control group. However, there were no significant differences between two groups in abdominal distension(RR = 0.79, 95%Cl:0.21 ~ 3.00, P = 0.72), stomatitis risk (RR = 1.23, 95%Cl: 0.48 ~ 3.21, P = 0.67), fatigue (SMD = -7.12, 95%Cl:-14.99 ~ 0.75, P = 0.08)and loss of appetite(SMD = -2.86, 95%Cl: -5.83 ~ 0.11, P = 0.06). Furthermore, the use of probiotics did not significantly improve the quality of life (QOL) (SMD = 8.82, 95%Cl: -1.11 ~ 18.75, P = 0.08)of colorectal cancer patients receiving chemoradiotherapy.

This meta-analysis suggested that probiotic consumption may ameliorate certain adverse reactions in patients with colorectal cancer receiving chemoradiotherapy.

Prospero registration number: PROSPERO (CRD42023465966).

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.

While studies of various carcinomas have reported aberrant metal metabolism, much remains unknown regarding their spatial accumulation and regulatory impacts in tumors. Here, elevated copper levels are detected in breast cancer tumors from patients and animal models, specifically exhibiting a zonate spatial pattern. Spatially resolved multiomics analyses reveal that copper zonation drives a tumor metabolic preference for oxidative phosphorylation (OXPHOS) over glycolysis and promotes tumor metastatic and immune-desert phenotypes. Then, a copper-depleting nanoagent is developed based on copper chelator tetrathiomolybdate (TM)-loaded hybridized bacterial outer membrane vesicles (hOMVs) from both Akkermansia muciniphila bacteria and CD326-targeting peptide-engineered Escherichia coli (TM@CD326hOMV). Systemic administration of TM@CD326hOMV reduces the labile copper level in tumors and inhibits both tumor growth and metastatic phenotypes, specifically through metabolic reprograming of OXPHOS toward glycolysis and restoration of antitumor immunity responses involving natural killer cells, CD4+ T cells, and cytotoxic CD8+ T cells in tumors. Assessing survival in murine breast cancer models, a combination of TM@CD326hOMV and a checkpoint blockade agent outperforms monotherapies. Notably, a copper-rich diet undermines the therapeutic efficacy of TM@CD326hOMV. Beyond demonstrating an effective nanoagent for treating breast cancer, this study deepens the understanding of how the pattern of copper accumulation in tumors affects pathophysiology and immunity.

Immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 blockade, have shown great success in treating melanoma. PD-L1 (B7-H1, CD274), a ligand of PD-1, binds to PD-1 on T cells, inhibiting their activation and proliferation through multiple pathways, thus dampening tumor-reactive T cell activity. Studies have linked PD-L1 expression in melanoma with tumor growth, invasion, and metastasis, making the PD-1/PD-L1 pathway a critical target in melanoma therapy. However, immune-related adverse events are common, reducing the effectiveness of anti-PD-L1 treatments. Recent evidence suggests that the gut microbiome significantly influences anti-tumor immunity, with the microbiome potentially reprogramming the tumor microenvironment and overcoming resistance to anti-PD-1 therapies in melanoma patients. This review explores the mechanisms of PD-1/PD-L1 in melanoma and examines how gut microbiota and its metabolites may help address resistance to anti-PD-1 therapy, offering new insights for improving melanoma treatment strategies.

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.

Hepatocellular carcinoma (HCC) is a malignant form of primary liver cancer. Intricate networks linked to the host immune system may be associated with the pathogenesis of HCC. A huge amount of interdisciplinary medical information for the treatment of HCC has been accumulated over recent years. For example, advances in new immunotherapy have improved the results of treatment for HCC. This approach can be advantageously combined with standard conventional treatments such as surgical resection to improve the therapeutic effect. However, several toxic effects of treatments may pose a significant threat to human health. Now, a shift in mindset is important for achieving superior cancer therapy, where probiotic therapy may be considered, at least within the bounds of safety. The interplay between the gut microbiota and immune system could affect the efficacy of several anticancer treatments, including of immune checkpoint therapy via the alteration of Th17 cell function against various malignant tumors. Here, some recent anticancer techniques are discussed, whereby the growth of HCC may be effectively and safely repressed by probiotic 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.

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.

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.

Gastric cancer (GC) is linked to high morbidity and mortality rates. Approximately two-thirds of GC patients are diagnosed at an advanced or metastatic stage. Conventional treatments for GC, including surgery, radiotherapy, and chemotherapy, offer limited prognostic improvement. Recently, immunotherapy has gained attention for its promising therapeutic effects in various tumors. Immunotherapy functions by activating and regulating the patient's immune cells to target and eliminate tumor cells, thereby reducing the tumor burden in the body. Among immunotherapies, immune checkpoint inhibitors (ICIs) are the most advanced. ICIs disrupt the inhibitory protein-small molecule (PD-L1, CTLA4, VISTA, TIM-3 and LAG3) interactions produced by immune cells, reactivating these cells to recognize and attack tumor cells. However, adverse reactions and resistance to ICIs hinder their further clinical and experimental development. Therefore, a comprehensive understanding of the advancements in ICIs for GC is crucial. This article discusses the latest developments in clinical trials of ICIs for GC and examines combination therapies involving ICIs (targeted therapy, chemotherapy, radiotherapy), alongside ongoing clinical trials. Additionally, the review investigates the tumor immune microenvironment and its role in non-responsiveness to ICIs, highlighting the function of tumor immune cells in ICI efficacy. Finally, the article explores the prospects and limitations of new immunotherapy-related technologies, such as tumor vaccines, nanotechnologies, and emerging therapeutic strategies, aiming to advance research into personalized and optimized immunotherapy for patients with locally advanced gastric cancer.

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.

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.

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.

Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) pose a significant threat to human health worldwide, characterized by intricate pathogenesis. A PC-esterase domain containing 1A (PCED1A) is a critical number of the GDSL/SGNH superfamily.

The aim of this study is to explore the diagnostic value of PCED1A in HCC and CRC and its relationship with immune infiltration.

The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) database, the Cancer Cell Line Encyclopedia database (CCLE), and the Human Protein Atlas (HPA) were used to detect the expression of PCED1A in tissues and cells. Cibersoft, Timer, and Xcell were used to analyze the effect of PCED1A on immune cell infiltration. The relationship between PCED1A and the immune checkpoint was analyzed. The coexpression analysis of PCED1A was conducted using the LinkedOmics database.

PCED1A was increased in HCC and CRC with poor prognosis. Immunohistochemistry demonstrated that PCED1A was highly expressed in HCC and CRC compared to corresponding normal tissues. PCED1A expression was related to poor overall survival (OS) and progression-free survival (PFS). High PCED1A expression was strongly associated with M2 macrophages, impacting HCC progression. Conversely, low PCED1A expression was closely related to Th2 cells in CRC. In addition, the checkpoint named PDCD1 showed a good correlation with PCED1A high expression group in HCC and CRC. Lastly, the PCED1A and ZNF family showed a complex and intertwined relationship through coexpression analysis on the LinkedOmics database.

PCED1A, related to tumor immune infiltration, is a promising diagnostic biomarker and a valuable therapeutic target for HCC and CRC.

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.

immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic urothelial carcinoma (mUC), significantly improving survival outcomes. However, a subset of patients do not respond to ICIs, prompting research into potential predictive factors. Commonly prescribed medications such as corticosteroids, proton-pump inhibitors (PPIs), antibiotics (Abs), antihypertensives, and analgesics may influence ICI effectiveness.

we conducted a literature search on PubMed to investigate the impact of concomitant medications on the outcomes of patients with mUC, treated with ICIs. We selected the most relevant studies and performed a narrative review.

corticosteroids, PPIs and Abs have been associated with reduced survival in ICI-treated patients, including those with mUC. In contrast, antihypertensive agents like renin-angiotensin system inhibitors and beta-blockers may enhance ICI efficacy, though evidence remains inconclusive. The impact of other medications, such as statins, metformin, and analgesics, on ICI outcomes is less clear, with some data suggesting a detrimental impact on immune response.

this narrative review synthesizes current evidence on how concomitant medications affect outcomes in mUC patients treated with ICIs.

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

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.

The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8+ T cell activation without exhaustion. Various strains of Christensenella minuta selectively boost the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase 2 study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential.