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

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.

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.

Post‑translational modifications (PTMs) of proteins influence their functionality by altering the structure of precursor proteins. These modifications are closely linked to tumor progression through the regulation of processes such as cell proliferation, apoptosis, angiogenesis and invasion. Tumors produce large amounts of lactic acid through aerobic glycolysis. Lactic acid not only serves an important role in cell metabolism, but also serves an important role in cell communication. Lactylation, a PTM involving lactate and lysine residues as substrates, serves as an epigenetic regulator that modulates intracellular signaling, gene expression and protein function, thereby serving a crucial role in tumorigenesis and progression. The identification of lactylation provides a key breakthrough in elucidating the interaction between tumor metabolic reprogramming and epigenetic modification. The present review primarily summarizes the occurrence of lactylation, its effect on tumor progression, drug resistance, the tumor microenvironment and gut microbiota, and its potential as a therapeutic target for cancer. The aim of the present review was to provide novel strategies for potential cancer therapies.

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.

Colorectal cancer (CRC) is one of the most prevalent and lethal cancers worldwide, ranking third in incidence and second in mortality. While immunotherapy has shown promise in patients with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), its effectiveness in proficient mismatch repair (pMMR) or microsatellite stable (MSS) CRC remains limited. Recent advances highlight the gut microbiota as a potential modulator of anti-tumor immunity. The gut microbiome can significantly influence the efficacy of immune checkpoint inhibitors (ICIs), especially in pMMR/MSS CRC, by modulating immune responses and systemic inflammation. This review explores the role of the gut microbiota in pMMR/MSS CRC, the mechanisms by which it may enhance immunotherapy, and current strategies for microbiota modulation. We discuss the potential benefits of combining microbiota-targeting interventions with immunotherapy to improve treatment outcomes for pMMR/MSS CRC patients.

The gut microbiome is interlinked with renal cell carcinoma (RCC) and its response to systemic treatment. Mounting data suggests that certain elements of the gut microbiome may correlate with improved outcomes. New generation sequencing techniques and advanced bioinformatic data curation are accelerating the investigation of specific markers and metabolites that could predict treatment response. A variety of new therapeutic strategies, such as fecal microbiota transplantation, probiotic supplements, and dietary interventions, are currently being developed to modify the gut microbiome and improve anticancer therapies in patients with RCC. This review discusses the preliminary evidence indicating the role of the microbiome in cancer treatment, the techniques and tools necessary for its proper study and some of the current forms with which the microbiome can be modulated to improve patient outcomes.

The gut microbiota exhibits intricate connections with the body's immune system and holds significant implications for various diseases and cancers. Currently, accumulating evidence suggests a correlation between the composition of the gut microbiota and the development, treatment, and prognosis of melanoma. However, the underlying pathogenesis remains incompletely elucidated. In this comprehensive review, we present an in-depth review of the role played by gut microbiota in melanoma tumorigenesis, growth, metastasis, treatment response, and prognosis. Furthermore, we discuss the potential utility of gut microbiota as a promising prognostic marker. Lastly, we summarize three routes through which gut microbiota influences melanoma: immunity, aging, and the endocrine system. By modulating innate and adaptive immunity in patients with melanoma across different age groups and genders, the gut microbiota plays a crucial role in anti-tumor immune regulation from tumorigenesis to prognosis management, thereby impacting tumor growth and metastasis. This review also addresses current study limitations while highlighting future research prospects.

Although immune checkpoint inhibitors (ICIs) are widely used in clinical oncology, less than half of treated cancer patients derive benefit from this therapy. Both tumor- and host-related variables are implicated in response to ICIs. The predictive value of PD-L1 expression is confined only to several cancer types, so this molecule is not an agnostic biomarker. Highly elevated tumor mutation burden (TMB) caused either by excessive carcinogenic exposure or by a deficiency in DNA repair is a reliable indicator for ICI efficacy, as exemplified by tumors with high-level microsatellite instability (MSI-H). Other potentially relevant tumor-related characteristics include gene expression signatures, pattern of tumor infiltration by immune cells, and, perhaps, some immune-response modifying somatic mutations. Host-related factors have not yet been comprehensively considered in relevant clinical trials. Microbiome composition, markers of systemic inflammation [e.g., neutrophil-to-lymphocyte ratio (NLR)], and human leucocyte antigen (HLA) diversity may influence the efficacy of ICIs. Studies on ICI biomarkers are likely to reveal modifiable tumor or host characteristics, which can be utilized to direct the antitumor immune defense. Examples of the latter approach include tumor priming to immune therapy by cytotoxic drugs and elevation of ICI efficacy by microbiome modification.

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.

Extensive studies have shown that gut microbiota-derived metabolites can enhance the antitumor efficacy of immunotherapy by modulating host immune responses. However, the more comprehensive spectrum of such metabolites and their mechanisms remain unclear. In this study, we demonstrated that L-selenomethionine (L-SeMet), a gut microbial metabolite, acts as a positive regulator of immunotherapy. Through screening of a repository of gut microbial metabolites, we identified that L-SeMet can effectively enhance the effector function of CD8+ T cells. Furthermore, intragastric administration of L-SeMet in mice significantly suppressed the growth of subcutaneous MC38 tumors. Mechanistically, L-SeMet enhances T cell receptor (TCR) signaling by promoting LCK phosphorylation. Collectively, our findings reveal that the gut microbial metabolite L-SeMet inhibits colorectal tumor growth by potentiating CD8+ T cell functions, providing a potential therapeutic strategy for colorectal cancer treatment.

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.

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.

Immune checkpoint blockade (ICB) inhibits tumor immune escape and has significantly advanced tumor therapy. However, ICB benefits only a minority of patients treated and may lead to many immune-related adverse events. Therefore, identifying factors that can predict treatment outcomes, enhance synergy with ICB, and mitigate immune-related adverse events is urgently needed.

Tertiary lymphoid structures (TLS) are ectopic lymphoid tissues that arise from the tumor periphery. They have been found to be associated with better prognosis and improved clinical outcomes after ICB therapy. TLS may help address the problems associated with ICB. The multiple mechanisms of action between TLS and ICB remain unknown. This paper described potential mechanisms of interaction between the two and explored their potential applications.

The standard first-line treatment for driver-gene negative advanced non-small cell lung cancer (NSCLC) is chemotherapy combined with immunotherapy. However, owing to the immune microenvironment imbalance and immune status impairment caused by repeated chemotherapy, as well as the primary or secondary resistance to immune checkpoint inhibitors, the efficacy of immunotherapy combined with chemotherapy remains unsatisfactory. Recent studies have shown that faecal microbiota transplantation (FMT) can modulate the intestinal microflora, influence the tumour immune microenvironment and even enhance the efficacy of immunotherapy. Hence, we conduct such a prospective, exploratory study to evaluate the efficacy and safety of integrating FMT with standard first-line treatment in patients with driver-gene negative advanced NSCLC.

FMT-JSNO-02 (NCT06403111) is a prospective, multicentre, single-arm exploratory study. It is planned to include 62 cases of previously untreated driver-gene negative, Eastern Cooperative Oncology Group Performance Status 0-1, programmed death ligand 1<50% advanced NSCLC patients, who will be given FMT by orally ingested stool capsules on the basis of standard first-line treatment of chemotherapy combined with immunotherapy. The primary endpoint of this study is the 12-month progression-free survival rate.

The study was approved by the ethics committee of the Second People's Hospital of Changzhou (number [2024] YLJSA005) and is being conducted in accordance with the principles of the Declaration of Helsinki. The results of this study will be disseminated through publication in a peer-reviewed journal and presentation at scientific conferences.

NCT06403111. Date of registration: 7 May 2024, the first version protocol.

Cancer immunotherapy has been successful in patients with different types of cancers, but its efficacy in treating certain types of colorectal cancer (CRC) is limited. The aim of this study was to explore whether sea cucumber polysaccharides (SCP) could impact resistance to anti-programmed cell death-1 (anti-PD1) immunotherapy of CRC and the role of microbiota in mediating their effects. Mice inoculated with immunotherapy resistant CT-26 CRC cells were pretreated with SCP, followed by treatment with/without the anti-PD1 antibody. SCP alone exhibited no inhibitory effect on tumor growth, but they drastically enhanced the efficacy of anti-PD1 treatment, which alone showed minimal effect on tumor development. Compared to anti-PD1 only treatment, a combination of SCP and anti-PD1 increased CD8+ T cells, especially IFN-γ+ cytotoxic CD8+ T cells, and decreased regulatory CD4+ T cells. SCP modulated gut microbiota and increased the relative abundance of bacteria including Bifidobacterium and Faecalibaculum. A fecal microbiota transplantation experiment showed that the sensitizing effect of SCP was at least partly mediated by microbiota. Furthermore, oral supplementation of Bifidobacterium pseudolongum or Faecalibaculum rodentium recapitulated the beneficial effect of SCP in potentiating anti-PD1 efficacy. Altogether, these findings demonstrated that SCP could be potentially developed as a dietary adjuvant to increase the efficacy of immunotherapy in CRC.

Immune checkpoint inhibitors (ICIs) have been approved for treatment of microsatellite instable (MSI-H) metastatic colorectal cancer (mCRC), but factors associated with receipt and efficacy of ICIs in routine clinical practice remain largely unknown.

To identify factors associated with receipt of ICIs and associated survival outcomes among patients with mCRC in routine clinical practice.

This population-based cohort study used deidentified data from a nationwide electronic health record-derived database to include 18 932 patients diagnosed with mCRC between January 2013 and June 2019. Population-based patients were diagnosed with de novo mCRC and had at least 2 documented clinical visits on or after the date of diagnosis. The study analyses were performed between September 2020 and April 2021.

Patients received ICI therapy and/or chemotherapy as part of a systemic treatment for mCRC.

The outcomes were receipt of ICI therapy, overall survival (OS), and time to treatment discontinuation (TTD).

In this cohort study of 18 932 patients diagnosed with mCRC (10 537 [55.7%] male; 546 [2.9%] Asian, 2005 [10.6%] Black or African American, 1674 [8.8%] Hispanic, 12 338 [65.2%] White, 4043 [21.4%] unknown race or ethnicity; median [IQR] age at metastatic diagnosis, 64.6 [55.0-73.3] years), patients with MSI-H tumors had a significantly higher probability of receiving ICIs than those with microsatellite stable (MSS) tumors (odds ratio [OR], 22.66 [95% CI, 17.30-29.73]; P < .001), whereas patients initially diagnosed with synchronous mCRC had significantly lower odds of receiving ICIs than patients with metachronous mCRC (OR, 0.57 [95% CI, 0.45-0.73]; P < .001). Patients with MSI-H tumors who received ICIs as first line of therapy had significantly longer OS than those receiving chemotherapy only (HR, 0.37 [95% CI, 0.25-0.56]; P < .001). Among patients with MSS tumors, ICI-based therapy was associated with significantly longer OS for patients with high albumin level (vs low: HR, 0.28 [95% CI, 0.18-0.45]; P < .001) and antibiotic use (vs nonuse: HR, 0.43 [95% CI, 0.27-0.67]; P < .001), but a significantly shorter OS for patients with synchronous mCRC (vs metachronous: HR, 1.90 [95% CI, 1.24-2.89]; P = .003). In addition, 29 out of 235 patients with MSS tumors (12.3%) experienced durable responses on ICI-based therapy. Similar patterns of associations with TTD were observed.

In this cohort study of patients with mCRC, clinical characteristics were associated with different survival outcomes in patients treated with ICI-based therapy, with important clinical implications for patients with MSS tumors who are generally unresponsive to immunotherapy.

Cancer immunotherapy has revolutionized cancer treatment, but therapeutic ineffectiveness-driven by the tumor microenvironment and immune evasion mechanisms-continues to limit its clinical efficacy. This challenge underscores the need to explore innovative approaches, such as multimodal immunotherapy. Phytochemicals, bioactive compounds derived from plants, have emerged as promising candidates for overcoming these barriers due to their immunomodulatory and antitumor properties. This review explores the synergistic potential of phytochemicals in enhancing immunotherapy by modulating immune responses, reprogramming the tumor microenvironment, and reducing immunosuppressive factors. Integrating phytochemicals with conventional immunotherapy strategies represents a novel approach to mitigating resistance and enhancing therapeutic outcomes. For instance, nab-paclitaxel has shown the potential in overcoming resistance to immune checkpoint inhibitors, while QS-21 synergistically enhances the efficacy of tumor vaccines. Furthermore, we highlight recent advancements in leveraging nanotechnology to engineer phytochemicals for improved bioavailability and targeted delivery. These innovations hold great promise for optimizing the clinical application of phytochemicals. However, further large-scale clinical studies are crucial to fully integrate these compounds into immunotherapeutic regimens effectively.

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.

Melanoma, a highly aggressive form of skin cancer, has seen significant advancements in treatment through the introduction of immunotherapy. However, the variability in patient responses underscores the need for reliable biomarkers to guide treatment decisions. This article reviews key biomarkers in melanoma immunotherapy, such as PD-L1 expression, tumor mutational burden (TMB), and gene expression profiles (GEPs). It also explores emerging biomarkers, including LAG-3 expression, immune cell phenotyping in tissue and blood, gut microbiota, and circulating tumor DNA (ctDNA). Notably, ctDNA may offer valuable insights into the efficacy of T cell-engaging bispecific molecules, such as tebentafusp. The review provides a comprehensive overview of the evolving landscape of melanoma biomarkers, their role in personalizing treatment, and future research directions, including neoadjuvant immune checkpoint inhibition.

The intestinal microbiota has major influence on human physiology and modulates health and disease. Complex host-microbe interactions regulate various homeostatic processes, including metabolism and immune function, while disturbances in microbiota composition (dysbiosis) are associated with a plethora of human diseases and are believed to modulate disease initiation, progression and therapy response. The vast complexity of the human microbiota and its metabolic output represents a great challenge in unraveling the molecular basis of host-microbe interactions in specific physiological contexts. To increase our understanding of these interactions, functional microbiota research using animal models in a reductionistic setting are essential. In the dynamic landscape of gut microbiota research, the use of germ-free and gnotobiotic mouse technology, in which causal disease-driving mechanisms can be dissected, represents a pivotal investigative tool for functional microbiota research in health and disease, in which causal disease-driving mechanisms can be dissected. A better understanding of the health-modulating functions of the microbiota opens perspectives for improved therapies in many diseases. In this review, we discuss practical considerations for the design and execution of germ-free and gnotobiotic experiments, including considerations around germ-free rederivation and housing conditions, route and timing of microbial administration, and dosing protocols. This comprehensive overview aims to provide researchers with valuable insights for improved experimental design in the field of functional microbiota research.

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.

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.

Cancer vaccines, aimed at evolving the human immune system to eliminate tumor cells, have long been explored as a method of cancer treatment with significant clinical potential. Traditional delivery systems face significant challenges in directly targeting tumor cells and delivering adequate amounts of antigen due to the hostile tumor microenvironment. Emerging evidence suggests that certain bacteria naturally home in on tumors and modulate antitumor immunity, making bacterial vectors a promising vehicle for precision cancer vaccines. Live bacterial vehicles offer several advantages, including tumor colonization, precise drug delivery, and immune stimulation, making them a compelling option for cancer immunotherapy. In this review, we explore the mechanisms of action behind living bacteria-based vaccines, recent progress in popular bacterial chassis, and strategies for specific payload delivery and biocontainment to ensure safety. These approaches will lay the foundation for developing an affordable, widely applicable cancer vaccine delivery system. This review also discusses the challenges and future opportunities in harnessing bacterial-based vaccines for enhanced therapeutic outcomes in cancer treatment.

Antibiotic therapy (ABT)-induced dysbiosis may affect the efficacy of immune checkpoint inhibitors (ICI) therapy. We investigated the association between ABT and real-world overall survival (rwOS) and progression-free survival (rwPFS) in patients with metastatic urothelial carcinoma (mUC) receiving ICI or cisplatin-based chemotherapy (CIS).

Three thousand, one hundred seventy-nine patients were included from a nationwide electronic health record-derived de-identified database. Three-month landmark Kaplan-Meier methods and log-rank tests were used to estimate rwOS/PFS between treatment modalities based on ABT groups (stratified by exposure, timing, excretion mode, and administration route). Cox proportional models with time-varying coefficients were used to investigate the associations between ABT, treatment modality, and rwOS/PFS.

A total of 402 (27.1%) ICI and 655 (38.6%) CIS patients received ABT (p < 0.001). ICI receipt (OR 0.65, p < 0.001) and advanced age (OR 0.98, p < 0.001) were associated with lower ABT use. ICI exclusive findings included a negative correlation with rwOS in patients who received post-treatment initiated (ICI median: pre-13.2 vs post-7.9 vs none-13.3 months; p = 0.009), oral (median oral-9.6 vs none-13.3 months, p = 0.03), and renally cleared (median renal-9.9 vs none-13.3 months, p = 0.04) ABT. ABT's effect was negatively associated with rwOS in ICI patients within first 6 months (HR 1.36, 95% CI 1.107-1.74, p = 0.01) but not thereafter (p = 0.7).

This study identified a potential ICI-specific negative correlation between ABT and rwOS in patients with mUC, specifically those exposed to ABT pills and receipt before treatment initiation. These results emphasize the importance of antibiotic stewardship and continued investigation of the role of gut microbiome in mUC treatment efficacy.

Tumors are inherently embedded in systemic physiology, which contributes metabolites, signaling molecules, and immune cells to the tumor microenvironment. As a result, any systemic change to host metabolism can impact tumor progression and response to therapy. In this review, we explore how factors that affect metabolic health, such as diet, obesity, and exercise, influence the interplay between cancer and immune cells that reside within tumors. We also examine how metabolic diseases influence cancer progression, metastasis, and treatment. Finally, we consider how metabolic interventions can be deployed to improve immunotherapy. The overall goal is to highlight how metabolic heterogeneity in the human population shapes the immune response to cancer.

In recent years, numerous reports have been published regarding the relationship between the gut microbiota and the tumor immune microenvironment (TIME). However, to date, no systematic study has been conducted on the relationship between gut microbiota and the TIME using bibliometric methods.

To describe the current global research status on the correlation between gut microbiota and the TIME, and to identify the most influential countries, research institutions, researchers, and research hotspots related to this topic.

We searched for all literature related to gut microbiota and TIME published from January 1, 2014, to May 28, 2024, in the Web of Science Core Collection database. We then conducted a bibliometric analysis and created visual maps of the published literature on countries, institutions, authors, keywords, references, etc., using CiteSpace (6.2R6), VOSviewer (1.6.20), and bibliometrics (based on R 4.3.2).

In total, 491 documents were included, with a rapid increase in the number of publications starting in 2019. The country with the highest number of publications was China, followed by the United States. Germany has the highest number of citations in literature. From a centrality perspective, the United States has the highest influence in this field. The institutions with the highest number of publications were Shanghai Jiao Tong University and Zhejiang University. However, the institution with the most citations was the United States National Cancer Institute. Among authors, Professor Giorgio Trinchieri from the National Institutes of Health has the most local impact in this field. The most cited author was Fan XZ. The results of journal publications showed that the top three journals with the highest number of published papers were Frontiers in Immunology, Cancers, and Frontiers in Oncology. The three most frequently used keywords were gut microbiota, tumor microenvironment, and immunotherapy.

This study systematically elaborates on the research progress related to gut microbiota and TIME over the past decade. Research results indicate that the number of publications has rapidly increased since 2019, with research hotspots including "gut microbiota", "tumor microenvironment" and "immunotherapy". Exploring the effects of specific gut microbiota or derived metabolites on the behavior of immune cells in the TIME, regulating the secretion of immune molecules, and influencing immunotherapy are research hotspots and future research directions.

Vitiligo is a cutaneous autoimmune disorder characterized by progressive depigmentation due to melanocyte destruction by cytotoxic T cells. Genetic factors predispose patients to the disease and are supported by environmental factors that often initiate new disease episodes. We investigated whether disease outcomes were partially defined by pathogenic microbes that drive nutrient deficiency and inflammation. Our study presents the results of research on the diet and gut microbiome composition of patients with vitiligo and healthy controls from Kazakhstan and the United States. Dietary nutrient intake was assessed using the National Institutes of Health-generated Diet History Questionnaire. Patients with active vitiligo exhibit a limited intake of specific fatty acids, amino acids, fiber, and zinc. Disease activity was further characterized by the abundance of Odoribacter and Escherichia in the gut. Metabolic pathway analysis supported the role of the Escherichia genus in disease activity by limiting energy metabolism and amino acid biosynthetic pathways. Disease activity was also associated with elevated circulating proinflammatory cytokines. These findings suggest that nutritional limitations are not compensated by metabolites from the gut microbiome in active disease, potentially leaving room for inflammation and exacerbating vitiligo. The intricate relationship among diet, gut microbiome composition, and disease progression in vitiligo highlights potential avenues for targeted interventions to reduce autoimmune activity and improve patient outcomes.

Immunomodulating effects of Helicobacter pylori (H. pylori) have been shown to inhibit antitumor immunity. Resistance to immune checkpoint inhibitor (ICI)-based therapies is common among patients with hepatocellular carcinoma (HCC). This study aimed to assess the effect of H. pylori on the outcomes of ICI in patients with HCC.

We conducted a multicenter study in patients with HCC across a broad range of treatments. Patients received either ICI-based combination regimens or sorafenib-based therapy. H. pylori serostatus and virulence factors were determined and correlated with overall survival (OS), progression-free survival (PFS), and safety across the treatment modalities.

180 patients with HCC were included; among these, 64 were treated with ICI-based regimen and 116 with sorafenib-based regimen. In patients treated with ICI, median OS was shorter in H. pylori-positive patients (10.9 months in H. pylori-positive vs. 18.3 months; p = 0.0384). H. pylori positivity was associated with a shorter PFS in ICI recipients (3.9 months vs. 6.8 months, p = 0.0499). In patients treated with sorafenib, median OS was not shorter among H. pylori-positive patients (13.4 months in H. pylori-positive vs. 10.6 months; p = 0.3353). Immune-related adverse events and rates of gastrointestinal bleeding were comparable between H. pylori-positive and -negative patients.

H. pylori seropositivity was linked to poorer outcomes in patients with HCC treated with ICI. This association was not observed among patients receiving sorafenib-based therapies.

Microalgae present a novel and multifaceted approach to cancer therapy by modulating the tumor-associated microbiome (TAM) and the tumor microenvironment (TME). Through their ability to restore gut microbiota balance, reduce inflammation, and enhance immune responses, microalgae contribute to improved cancer treatment outcomes. As photosynthetic microorganisms, microalgae exhibit inherent anti-tumor, antioxidant, and immune-regulating properties, making them valuable in photodynamic therapy and tumor imaging due to their capacity to generate reactive oxygen species. Additionally, microalgae serve as effective drug delivery vehicles, leveraging their biocompatibility and unique structural properties to target the TME more precisely. Microalgae-based microrobots further expand their therapeutic potential by autonomously navigating complex biological environments, offering a promising future for precision-targeted cancer treatments. We position microalgae as a multifunctional agent capable of modulating TAM, offering novel strategies to enhance TME and improve the efficacy of cancer therapies.

Patient responses to immune checkpoint inhibitors can be influenced by the gastrointestinal microbiome. Mouse models can be used to study microbiome-host crosstalk, yet their utility is constrained by substantial anatomical, functional, immunological and microbial differences between mice and humans. Here we show that a gut-on-a-chip system mimicking the architecture and functionality of the human intestine by including faecal microbiome and peristaltic-like movements recapitulates microbiome-host interactions and predicts responses to immune checkpoint inhibitors in patients with melanoma. The system is composed of a vascular channel seeded with human microvascular endothelial cells and an intestinal channel with intestinal organoids derived from human induced pluripotent stem cells, with the two channels separated by a collagen matrix. By incorporating faecal samples from patients with melanoma into the intestinal channel and by performing multiomic analyses, we uncovered epithelium-specific biomarkers and microbial factors that correlate with clinical outcomes in patients with melanoma and that the microbiome of non-responders has a reduced ability to buffer cellular stress and self-renew. The gut-on-a-chip model may help identify prognostic biomarkers and therapeutic targets.

Resistance to anti-PD-1 therapy in melanoma remains a major obstacle in achieving effective and durable treatment outcomes, highlighting the need to understand and address the underlying mechanisms. The first key factor is innate anti-PD-1 resistance signature (IPRES), an expression of a group of genes associated with tumor plasticity and immune evasion. IPRES promotes epithelial-to-mesenchymal transition (EMT), increasing melanoma cells' invasiveness and survival. Overexpressed AXL, TWIST2, and WNT5a induce phenotypic changes. The upregulation of pro-inflammatory cytokines frequently coincides with EMT-related changes, further promoting a resistant and aggressive tumor phenotype. Inflamed tumor microenvironment may also drive the expression of resistance. The complexity of immune resistance development suggests that combination therapies are necessary to overcome it. Furthermore, targeting epigenetic regulation and exploring novel approaches such as miR-146a modulation may provide new strategies to counter resistance in melanoma.

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

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

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

Intestinal bacteria form one of the most complex microbial communities in the human body, playing a crucial role in maintaining host health and contributing to the development of various diseases. Here, we provide a comprehensive overview of the composition and function of intestinal bacteria, the factors affecting their homeostasis, and their association and mechanisms with a range of diseases (e.g., inflammatory bowel diseases, colorectal cancer, metabolic diseases). Additionally, their advanced potential in disease diagnosis and treatment is highlighted. Therapies, such as chemotherapy, radiotherapy, and immunotherapy, are significantly impacted by intestinal bacteria, with research indicating that bacteria can enhance chemoimmunotherapy efficiency by affecting T cell recruitment and immune cell infiltration. Fecal microbiota transplantation has emerged as a promising option for treating recurrent Clostridium difficile infections and certain metabolic and neurological disorders. Gut bacteria-related serum metabolites serve as non-invasive indicators for diagnosing CRC, while fecal immunochemical tests offer promising applications in CRC screening. Future research is needed to better understand the causal relationships between intestinal bacteria and diseases, develop more precise diagnostic tools, and evaluate the effectiveness and safety of microbiome-targeted therapies in clinical treatment. This study provides deeper insights into the role of intestinal bacteria in human health and disease, providing a scientific basis for innovative therapeutic strategies that have the potential to transform the landscape of healthcare.

Over the past few years, the tumor microbiome is increasingly recognized for its multifaceted involvement in cancer initiation, progression, and metastasis. With the application of 16S ribosomal ribonucleic acid (16S rRNA) sequencing, the intratumoral microbiome, also referred to as tumor-intrinsic or tumor-resident microbiome, has also been found to play a significant role in the tumor microenvironment (TME). Understanding their complex functions is critical for identifying new therapeutic avenues and improving treatment outcomes. This review first summarizes the origins and composition of these microbial communities, emphasizing their adapted diversity across a diverse range of tumor types and stages. Moreover, we outline the general mechanisms by which specific microbes induce tumor initiation, including the activation of carcinogenic pathways, deoxyribonucleic acid (DNA) damage, epigenetic modifications, and chronic inflammation. We further propose the tumor microbiome may evade immunity and promote angiogenesis to support tumor progression, while uncovering specific microbial influences on each step of the metastatic cascade, such as invasion, circulation, and seeding in secondary sites. Additionally, tumor microbiome is closely associated with drug resistance and influences therapeutic efficacy by modulating immune responses, drug metabolism, and apoptotic pathways. Furthermore, we explore innovative microbe-based therapeutic strategies, such as engineered bacteria, oncolytic virotherapy, and other modalities aimed at enhancing immunotherapeutic efficacy, paving the way for microbiome-centered cancer treatment frameworks.

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

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

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

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