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.

The pathogenesis of cancer is closely related to the disruption of homeostasis in the human body. The gut microbiome plays crucial roles in maintaining the homeostasis of its host throughout lifespan. In recent years, a large number of studies have shown that dysbiosis of the gut microbiome is involved in the entire process of cancer initiation, development, and prognosis by influencing the host immune system and metabolism. Some specific intestinal bacteria promote the occurrence and development of cancers under certain conditions. Conversely, some other specific intestinal bacteria suppress the oncogenesis and progression of cancers, including inhibiting the occurrence of cancers, delaying the progression of cancers and boosting the therapeutic effect on cancers. The promoting effects of the gut microbiome on cancers have been comprehensively discussed in the previous review. This article will review the latest advances in the roles and mechanisms of gut microbiome in cancer suppression, providing a new perspective for developing strategies of cancer prevention and treatment.

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.

Cancer is a long-term illness that involves an imbalance in cellular and immune functions. It can be caused by a range of factors, including exposure to environmental carcinogens, poor diet, infections, and genetic alterations. Maintaining a healthy gut microbiome is crucial for overall health, and short-chain fatty acids (SCFAs) produced by gut microbiota play a vital role in this process. Recent research has established that alterations in the gut microbiome led to decreased production of SCFA's in lumen of the colon, which associated with changes in the intestinal epithelial barrier function, and immunity, are closely linked to colorectal cancer (CRC) development and its progression. SCFAs influence cancer progression by modifying epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNA functions thereby affecting tumor initiation and metastasis. This suggests that restoring SCFA levels in colon through microbiota modulation could serve as an innovative strategy for CRC prevention and treatment. This review highlights the critical relationship between gut microbiota and CRC, emphasizing the potential of targeting SCFAs to enhance gut health and reduce CRC risk.

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

The gut microbiota 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.

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

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

Emerging evidence suggests that harnessing the microbiome holds promise for innovative diagnostic and therapeutic strategies in the management of pancreatic cancer (PC). This study aims to systematically summarize the microbial markers associated with PC and assess their potential application in clinical outcome. Forty-one studies were included to assess the associations between microbial markers and PC. Among these, 13 were developed prediction models related to the microbiome in which the highest diagnostic and prognostic model belong to blood and intratumor markers, respectively. Notably, findings that utilize microbiotas from various body sites were elucidated, demonstrating their importance as unique signatures in biomarker discovery for diverse clinical applications. This review provides unique perspectives on overcoming challenges in PC by highlighting potential microbial-related markers as non-invasive approaches. Further clinical studies should evaluate the utility and accuracy of key indicators in the microbiome as a personalized tool for managing PC.

The Bifidobacterium genus is a prominent bacterial population in the gastrointestinal tract. Previous findings suggest that Bifidobacterium is linked to tumor suppression in mouse models of melanoma. Additionally, when combined with the programmed death-ligand 1 (PD-L1) antibody, it can enhance anti-tumor treatment by increasing tumor-specific T-cell responses and promoting infiltration of antigen-specific T cells into tumors. However, there is a lack of studies on Bifidobacterium in esophageal squamous cell carcinoma (ESCC). This study aimed to investigate the potential impact of Bifidobacterium on this cancer type.

We examined 213 samples from ESCC patients who underwent tumor resection. The presence of Bifidobacterium was confirmed using quantitative polymerase chain reaction and fluorescent in situ hybridization (FISH). Patient overall survival (OS) was analyzed with Bifidobacterium positivity. Tumor-infiltrating lymphocytes (TILs) were evaluated via hematoxylin and eosin stains, and immunohistochemistry was used to assess programmed death-1 (PD-1), PD-L1, cluster of differentiation 8 (CD8), and forkhead box P3 (FOXP3) expression. Nutritional status was evaluated via computed tomography scans.

Bifidobacterium positivity showed no correlation with patient OS or TIL levels; however, Bifidobacterium positivity in normal tissue was associated with lower FOXP3 levels, suggesting a potential role in upregulating anti-tumor immune responses. Patients with Bifidobacterium present in peritumor normal tissue exhibited better skeletal muscle area and volume. Conversely, Bifidobacterium positivity in tumor tissue was associated with poorer prognostic nutrition index values, likely due to decreased albumin levels.

Bifidobacterium can induce the upregulated anti-tumor immune response and is more prevalent in cases with good nutritional status.

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

Intestinal microbiota members of the Bifidobacterium genus are increasingly explored as probiotics and therapeutics. However, the paucity of genetic tools and the widespread restriction modification (RM) systems in Bifidobacterium limit our ability to genetically manipulate these bacteria. Here we established a CRISPR-Cas9 cytosine base editor system (cBEST) for portable genome editing in bifidobacteria. Harboring different promoters characterized in this study, these cBEST plasmids showed a range of editing efficiencies in different strains and genomic contexts, highlighting the importance of fine-tuning base editor and sgRNA expression. Additionally, we showed that disruption or bypass of RM systems dramatically improved editing efficiencies in otherwise hard-to-edit genomic loci and Bifidobacterium strains. Notably, we demonstrated the use of RM-disrupted Bifidobacterium longum strains for simultaneous assembly, amplification, and methylation of the all-in-one editing plasmids, greatly streamlining the workflow for high-efficiency base editing. Last but not least, we showed the portability of cBESTs using the same editing construct to disrupt a conserved metabolic gene in multiple Bifidobacterium species. Looking ahead, the ability to efficiently edit and engineer bifidobacterial genomes will give rise to new opportunities for research and applications toward improving human health.IMPORTANCEThe ability to genetically manipulate specific genes and biological pathways in Bifidobacterium is essential to unlocking their probiotic and therapeutic potential in human health applications. The DNA double-strand break-free CRISPR-Cas9 cytosine base editor system established in this work allows portable and efficient base editing in Bifidobacterium spp. We further showed that bypass of restriction modification systems significantly improved base editing efficiency, especially for hard-to-edit genomic loci and strains. This expanded Bifidobacterium genome editing toolbox should facilitate mechanistic investigations into the roles of Bifidobacterium in host physiology and disease.

The interaction between the gut microbiome and cancer chemotherapy has been extensively studied. However, the exact role of the vaginal microbiome in chemotherapy remains unknown. To address this issue, we established a colorectal cancer chemotherapy mouse model. Here, we confirmed that 5-fluorouracil induced dysbiosis in both the vaginal and gut microbiomes, presenting a new challenge for conventional chemotherapy. Therefore, we innovatively propose an "intestinal-vaginal" probiotics administration strategy, which involves the simultaneous delivery of probiotics to both the gut and vagina, aiming to enhance chemotherapy efficacy while alleviating dysbiosis and associated side effects. Our results indicate that, compared to gut-only probiotic intervention, "intestinal-vaginal" probiotics administration significantly enhanced the anticancer efficacy of 5-fluorouracil by upregulating the p53 pathway. Furthermore, regarding gastrointestinal side effects, "intestinal-vaginal" probiotics more effectively reduced the release of vomit-associated neurotransmitters (e.g., 5-HT and SP), while also alleviating mucositis by downregulating the NF-κB pathway. Additionally, "intestinal-vaginal" probiotics outperformed the oral probiotic by increasing beneficial microbiota and reducing pathogenic bacteria. Notably, regarding vaginal side effects, "intestinal-vaginal" probiotics significantly inhibited the NF-κB inflammatory pathway and pro-apoptotic proteins, and improved vaginal dysbiosis compared to vaginal-only probiotics. These findings provide the first evidence of the significant potential of the "intestinal-vaginal" probiotics delivery approach as an adjunctive cancer therapy, which offers a novel perspective on the synergistic interactions between host microbiota communities.

The tumour microenvironment (TME) exerts a profound influence on cancer progression and treatment outcomes. Recent investigations have elucidated the crucial role of intratumoural microbiota and their metabolites in shaping the TME and modulating anti-tumour immunity. This review critically assesses the influence of intratumoural microbial metabolites on the TME and cancer immunotherapy. We systematically analyse how microbial-derived glucose, amino acid, and lipid metabolites modulate immune cell function, cytokine secretion, and tumour growth. The roles of specific metabolites, including lactate, short-chain fatty acids, bile acids, and tryptophan derivatives, are comprehensively examined in regulating immune responses and tumour progression. Furthermore, we investigate the potential of these metabolites to augment the efficacy of cancer immunotherapies, with particular emphasis on immune checkpoint inhibitors. By delineating the mechanisms through which microbial metabolites influence the TME, this review provides insights into novel microbiome-based therapeutic strategies, thereby highlighting a promising frontier in personalised cancer medicine.

Although cancer chemopreventive agents have been confirmed to effectively protect high-risk populations from cancer invasion or recurrence, only over ten drugs have been approved by the U.S. Food and Drug Administration. Therefore, screening potent cancer chemopreventive agents is crucial to reduce the constantly increasing incidence and mortality rate of cancer. Considering the lengthy prevention process, an ideal chemopreventive agent should be nontoxic, inexpensive, and oral. Natural compounds have become a natural treasure reservoir for cancer chemoprevention because of their superior ease of availability, cost-effectiveness, and safety. The benefits of natural compounds as chemopreventive agents in cancer prevention have been confirmed in various studies. In light of this, the present review is intended to fully delineate the entire scope of cancer chemoprevention, and primarily focuses on various aspects of cancer chemoprevention based on natural compounds, specifically focusing on the mechanism of action of natural compounds in cancer prevention, and discussing in detail how they exert cancer prevention effects by affecting classical signaling pathways, immune checkpoints, and gut microbiome. We also introduce novel cancer chemoprevention strategies and summarize the role of natural compounds in improving chemotherapy regimens. Furthermore, we describe strategies for discovering anticancer compounds with low abundance and high activity, revealing the broad prospects of natural compounds in drug discovery for cancer chemoprevention. Moreover, we associate cancer chemoprevention with precision medicine, and discuss the challenges encountered in cancer chemoprevention. Finally, we emphasize the transformative potential of natural compounds in advancing the field of cancer chemoprevention and their ability to introduce more effective and less toxic preventive options for oncology.

Parabacteroides distasonis (P. distasonis) could regulate inflammatory markers, promote intestinal barrier integrity, and block tumor formation in colon. However, the regulatory effect of P. distasonis on non-small cell lung cancer (NSCLC) remains unknown. This study aimed to investigate the regulatory effect of P. distasonis on NSCLC and its impact on tumor immunity.

We first established a mouse model of Lewis lung cancer, and administered P. distasonis and intrabitoneal injection of anti-mouse PD-1 monoclonal antibody to assess the impact of P. distasonis on tumor immunity, and mouse intestinal barrier. Then, we explored the effect of P. distasonis on CD8+T cells and CXCL9 secretion mediated by tumor-associated macrophages (TAM). We used the TLR1/2 complex inhibitor CPT22 to evaluate its effect on macrophage activation. Finally, we explored the effect of P. distasonis on CD8+T cells and CXCL9 secreted by TAM in vivo.

In vivo, P. distasonis enhanced anti-tumor effects of anti-PD-1 in NSCLC mice, improved intestinal barrier integrity, recruited macrophages, and promoted M1 polarization. In vitro, CD86 and iNOS levels in BMDM were elevated and CD206 and Arg1 levels were suppressed in membrane fraction of P. distasonis (PdMb) group in comparison to Control group. With additional CPT22 pre-treatment, the levels of CD86 and iNOS in BMDM were reduced, and the levels of CD206 and Arg1 were increased. Compared to PBS group, P. distasonis group exhibited higher proportion of CD8+T cells in tumor tissues, along with increased positive proportion of GZMB and IFN-γ in CD8+T cells. Additionally, in comparison to Control group, PdMb group showed an elevated proportion of GZMB+T and IFN-γ+T cells within CD8+T cells, and secretion of IFN-γ, TNF-α, perforin, and GZMB in CD8+T cell supernatant increased. Moreover, the proportion of CXCL9+F4/80+ macrophages in tumor tissues was higher in P. distasonis group compared to PBS group. In comparison to Control group, CXCL9 protein level in BMDM and CXCL9 secretion level in BMDM supernatant were increased in PdMb group. Finally, P. distasonis enhanced CD8+T cell activity by secreting CXCL9 from macrophages in vivo.

P. distasonis promoted CXCL9 secretion of TAM and enhanced CD8+T cell activity to trigger anti-tumor immunity against anti-PD-1 treatment in NSCLC mice.

Pancreatic cancer (PC) presents a significant challenge in oncology because of its late-stage diagnosis and limited treatment options. The inadequacy of current screening methods has prompted investigations into stool-based assays and microbial classifiers as potential early detection markers. The gut microbiota composition of PC patients may be influenced by population differences, thereby impacting the accuracy of disease prediction. However, comprehensive profiling of the PC gut microbiota and analysis of these cofactors remain limited. Therefore, we analyzed the stool microbiota of 33 Finnish and 50 Iranian PC patients along with 35 Finnish and 34 Iranian healthy controls using 16S rRNA gene sequencing. We assessed similarities and differences of PC gut microbiota in both populations while considering sociocultural impacts and generated a statistical model for disease prediction based on microbial classifiers. Our aim was to expand the current understanding of the PC gut microbiota, discuss the impact of population differences, and contribute to the development of early PC diagnosis through microbial biomarkers.

Compared with healthy controls, PC patients presented reduced microbial diversity, with discernible microbial profiles influenced by factors such as ethnicity, demographics, and lifestyle. PC was marked by significantly higher abundances of facultative pathogens including Enterobacteriaceae, Enterococcaceae, and Fusobacteriaceae, and significantly lower abundances of beneficial bacteria. In particular, bacteria belonging to the Clostridia class, such as butyrate-producing Lachnospiraceae, Butyricicoccaceae, and Ruminococcaceae, were depleted. A microbial classifier for the prediction of pancreatic ductal adenocarcinoma (PDAC) was developed in the Iranian cohort and evaluated in the Finnish cohort, where it yielded a respectable AUC of 0.88 (95% CI 0.78, 0.97).

This study highlights the potential of gut microbes as biomarkers for noninvasive PC screening and the development of targeted therapies, emphasizing the need for further research to validate these findings in diverse populations. A comprehensive understanding of the role of the gut microbiome in PC could significantly enhance early detection efforts and improve patient outcomes.

Our study shows that Bifidobacterium spp. supplementation reduces lung damage in acute lung injury by enhancing immune cell activity and restoring thrombospondin-1 levels, offering a promising therapeutic approach for the treatment of ALI/ARDS.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are critical conditions characterized by severe lung inflammation and damage, often exacerbated by mechanical ventilation. Probiotics, particularly those containing Bifidobacterium spp. (Bifidus) have shown promise in modulating immune responses and reducing inflammation.

In this study, we investigated the effects of Bifidus supplementation in a mouse model of lipopolysaccharide induced ALI and ventilator-induced lung injury.

Our results demonstrate that Bifidus significantly ameliorates lung injury by enhancing efferocytosis and reducing pro-inflammatory cytokine levels. Single-cell RNA sequencing revealed significant changes in lung immune cell populations, particularly macrophages and monocytes, which showed increased efferocytosis activity and modulation of key signaling pathways such as TNF, MAPK and TLR. Notably, Bifidus feeding restored thrombospondin-1 levels in lung tissue, facilitating clearance of apoptotic cells and promoting resolution of inflammation.

Overall, our study highlights the potential of Bifidus as a therapeutic strategy to mitigate lung injury in ALI/ARDS.

Despite multimodal treatment options, most gastrointestinal cancers are still associated with high mortality rates and poor responsiveness to immunotherapy. The unprecedented efficacy of chimeric antigen receptor (CAR)-engineered T cells in the treatment of haematological malignancies raised interest in translating CAR T cell therapies to the treatment of gastrointestinal cancers. Treatment of solid cancers with canonical CAR T cells faces substantial challenges, including the dense architecture of the tumour tissue, the tolerogenic environment with low tumour-intrinsic immunogenicity, the rareness of targetable tumour-selective antigens, the antigenic heterogeneity of cancer cells, and the profound metabolic and immune cell disbalances. This Review provides an overview of CAR T cell trials in the treatment of gastrointestinal cancers, discussing considerations relating to safety, efficacy, potential reasons for failure and options for improving CAR T cells for the future. In addition, lessons regarding how to improve efficacy are drawn from CAR T cells armed with adjuvants that sustain their activation within the hostile environment and activate resident immune cells. As the field is rapidly evolving, current treatment modalities and editing CAR T cell functionalities are being refined towards a potentially more successful CAR T cell therapy for gastrointestinal cancers.

Immune checkpoint inhibitors (ICIs) have improved outcomes of patients with many different cancers. These antibodies target molecules such as programmed cell death 1 (PD-1) or cytotoxic T lymphocyte associated protein 4 (CTLA-4) which normally function to limit immune activity. Treatment with ICIs reactivates T cells to destroy tumor cells in a highly specific manner, which in some patients, results in dramatic remissions and durable disease control. Over the last decade, much effort has been directed at characterizing factors that drive efficacy and resistance to ICI therapy. Food and Drug Administration (FDA)-approved biomarkers for ICI therapy have facilitated more judicious treatment of cancer patients and transformed the field of precision oncology. Yet, adaptive immunity against cancers is complex, and newer data have revealed the potential utility of other biomarkers. In this review, we discuss the utility of currently approved biomarkers and highlight how emerging biomarkers can further improve the identification of patients who benefit from ICIs.

The gut microbiota plays a role in triggering innate immunity and regulating the immune microenvironment (IME) of hepatocellular carcinoma (HCC) by acting on various signaling receptors and transcription factors through its metabolites and related molecules. Furthermore, there is an increasing recognition of the gut microbiota as a potential therapeutic target for HCC, given its ability to modulate the efficacy of immune checkpoint inhibitors (ICIs).

This review will discuss the mechanisms of gut microbiota in modulating immunotherapy of HCC, the predictive value of efficacy, and the therapeutic strategies for modulating the gut microbiota in detail.

We conducted a systematic literature search in PubMed, Embase, Scopus, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Chinese databases for articles involving the influence of gut microbiota on HCC immunotherapy.

The mechanisms underlying the effect of gut microbiota on HCC immunotherapy include gut-liver axis, tumor immune microenvironment (TIME), and antibodies. Patients who benefit from ICIs exhibit a higher abundance of gut microbiota. Antibiotics, fecal microbiota transplantation (FMT), probiotics, and prebiotics are effective methods to regulate gut microbiota.

The strong connection between the liver and gut will provide numerous opportunities for the development of microbiome-based diagnostics, treatments, or prevention strategies for HCC patients.

Lung cancer is the leading cause of cancer-related deaths worldwide. Although immunotherapy such as anti-programmed death-1 and its ligand 1 (PD-1/L1) is a standard treatment for advanced non-small cell lung cancer (NSCLC), many patients do not derive benefit directly. Several studies have elucidated new strategies to improve the antitumor immune response through gut microbiota modulation. However, it remains largely debatable regarding how gut microbiota remotely affect lung cancer microenvironment and subsequently modulate immunotherapy response. Here we show that commensal Bifidobacterium-derived extracellular vesicles (Bif.BEVs) can modulate the therapeutic effect of anti-PD-1 therapy in NSCLC. These Bif.BEVs are up-taken by lung cancer cells predominantly via dynamin-dependent endocytosis and upregulate PD-L1 expression through TLR4-NF-κB pathway. They also efficiently penetrate murine intestinal and patient-derived lung cancer organoids. Oral gavage of these Bif.BEVs result in their accumulation in tumors in mice. Using a syngeneic mouse model, Bif.BEVs are found to synergize the anti-tumor effect of anti-PD-1 via modulation of key cytokines, immune response and oncogenic pathways, and increase in tumor-infiltrating CD8+ T cells. Our study therefore identifies a link between Bif.BEVs and the tumor microenvironment, providing an alternative mechanism to explain how gut microbiota can influence immunotherapy response, particularly in tumors located anatomically distant from the gut.

Humans are home to a diverse community of bacteria, many of which form symbiotic relationships with their host. Notably, tumors can also harbor their own unique bacterial populations that can influence tumor growth and progression. These bacteria, which selectively colonize hypoxic and acidic tumor microenvironments, present a novel therapeutic strategy to combat cancer. Advancements in synthetic biology enable us to safely and efficiently program therapeutic drug production in bacteria, further enhancing their potential. This review provides a comprehensive guide to utilizing bacteria for cancer treatment. We discuss key considerations for selecting bacterial strains, emphasizing their colonization efficiency, the delicate balance between safety and anti-tumor efficacy, and the availability of tools for genetic engineering. We also delve into strategies for precise spatiotemporal control of drug delivery to minimize adverse effects and maximize therapeutic impact, exploring recent examples of engineered bacteria designed to combat tumors. Finally, we address the underlying challenges and future prospects of bacterial cancer therapy. This review underscores the versatility of bacterial therapies and outlines strategies to fully harness their potential in the fight against cancer.

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.

The influence of gut microbes on aging has been reported in several studies, but the mediating pathways of gut microbiota, whether there is a causal relationship between the two, and biomarker screening and validation have not been fully discussed. In this study, Mendelian Randomization (MR) and Linkage Disequilibrium Score Regression (LDSC) are used to systematically investigate the associations between gut microbiota, three aging indicators, and 14 age-related diseases. Additionally, this study integrates machine learning algorithms to explore the potential of MR and LDSC methods for biomarker screening. Gut microbiota is found to be a potential risk factor for 14 age-related diseases. The causal effects of gut microbiota on chronic kidney disease, cirrhosis, and heart failure are partially mediated by aging indicators. Additionally, gut microbiota identified through MR and LDSC methods exhibit biomarker properties for disease prediction (average AUC = 0.731). These methods can serve as auxiliary tools for conventional biomarker screening, effectively enhancing the performance of disease models (average AUC increased from 0.808 to 0.832). This study provides evidence that supports the association between the gut microbiota and aging and highlights the potential of genetic correlation and causal relationship analysis in biomarker discovery. These findings may help to develop new approaches for healthy aging detection and intervention.

To assess the effect of half-dose chemotherapy (HDC) and standard-dose chemotherapy (SDC) on the intestinal microbiota and to investigate whether fecal microbiota transplantation (FMT) can restore the intestinal microecology to enhance the efficacy of chemoimmunotherapy containing an anti-PD- 1 antibody (PD1).

Lewis lung cancer (LLC) tumor-bearing mice were divided into six groups, including Control, HDC, SDC, SDC + FMT, SDC + PD1, and SDC + PD1 + FMT. After the treatment, analyses were conducted on intestinal microbiota using 16S rRNA sequencing, immune cells through flow cytometry, cytokines and chemokines via polymerase chain reaction (PCR), and programmed death-ligand 1 (PD-L1) expression in tumor tissues by immunohistochemistry.

Alpha and beta diversity of intestinal flora were not significantly different between HDC and SDC groups, nor was there a significant difference in the abundance of the top 10 species at the phylum, class, order, family, genus, or species levels. FMT increased both alpha and beta diversity and led to an increase in the abundance of Ruminococcus_callidus and Alistipes_finegoldii at the species level in mice receiving SDC + FMT. Besides, tumor growth was significantly slowed in SDC + PD1 + FMT compared to SDC + PD1 group, accompanied by an up-regulated Bacteroidetes/Firmicutes ratio, down-regulated abundance of Proteobacteria species (including Pseudolabrys, Comamonas, Alcaligenaceae, Xanthobacteraceae and Comamonadaceae), as well as Faecalicoccus of Firmicutes, the increased number of cDC1 cells, cDC2 cells, CD4+ T cells and CD8+ T cells in the peripheral blood, and IFN-γ+CD8+ T cells, IFN-γ, granzyme B, TNF-α, CXCL9 and CXCL10 in intestinal tissues.

There were no significant differences between HDC and SDC in their effects on the intestinal microbiota. FMT exhibited a beneficial impact on gut microbiota and improved the efficacy of chemoimmunotherapy, possibly associated with the increase of immune cells and the modulation of related cytokines and chemokines.

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.

Multiple myeloma (MM) is a hematological malignancy characterized by a poor prognosis. While certain probiotics have been shown to produce antitumor molecules that inhibit solid tumor progression, it remains unclear whether probiotic-derived compounds can exert similar effects on hematological tumors, such as MM. In this study, we screened the cell-free culture supernatants (CFCS) of 24 probiotic strains for antitumor effects against multiple myeloma (MM) cells and identified that the CFCS from Clostridium butyricum (C. butyricum) demonstrated the most significant reduction in MM cell viability. Further fractionation of this CFCS through reverse-phase and gel filtration chromatography revealed a high enrichment of butyrate in the antitumor fraction, as confirmed by gas chromatography-mass spectrometry. Butyrate reduced MM cell viability in a concentration-dependent manner. Butyrate was significantly more cytotoxic to RPMI-8226 cells than peripheral blood mononuclear cells (PBMCs) isolated from two non-cancerous individuals. In the xenograft model of RPMI-8226 cells, butyrate showed significant inhibition of tumor formation. Cell cycle analysis showed that butyrate induced G1 phase arrest and increased sub-G1 phase, suggesting DNA fragmentation. Western blot analysis demonstrated that butyrate treatment led to cleaved poly ADP-ribose polymerase (PARP) accumulation. Additionally, flow cytometry showed an increase in annexin V positive MM cells, indicating apoptosis. Butyrate also exhibited synergistic antitumor activity when combined with bortezomib, a proteasome inhibitor. These findings suggest that probiotic-derived molecules, including butyrate, may enhance the therapeutic effect of hematological malignancy, such as MM.

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

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

This retrospective study aims to evaluate the impact of antibiotics (ATBs) use on the efficacy of immunotherapy in patients with advanced hepatocellular carcinoma (HCC), providing insights into the prudent use of ATBs in patients undergoing immunotherapy.

We retrospectively collected data from patients with advanced HCC treated with immune checkpoint inhibitors (ICIs) at our institution between January 1, 2021, and December 30, 2023. Patients were divided into two groups based on ATBs use: an ATB group and a non-ATB group. Clinical baseline characteristics were analyzed, and survival curves were plotted using the Kaplan-Meier model. A Cox proportional hazards model was employed to analyze influencing factors.

Among the 102 advanced HCC patients receiving ICIs treatment, 29 were in the ATB group, and 73 were in the non-ATB group. The progression-free survival (PFS) (P = 0.034) and overall survival (OS) (P = 0.021) were significantly shorter in the ATB group compared to the non-ATB group. The difference in PFS between the two groups was associated with ATBs use and patients' AFP levels, while ATBs use was identified as an independent risk factor for the difference in OS between the groups.

ATB use in the context of immunotherapy for advanced HCC is associated with reduced PFS and OS. Caution is warranted in the administration of ATBs to patients undergoing immunotherapy.

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

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

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options and poor prognosis. The gut microbiota, a diverse community of microorganisms in the gastrointestinal tract, plays a crucial role in regulating immune responses through the gut-immune axis. Recent studies have highlighted its significant impact on TNBC progression and the efficacy of immunotherapies. This review examines the interactions between gut microbiota and the immune system in TNBC, focusing on key immune cells and pathways involved in tumor immunity. It also explores microbiota modulation strategies, including probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation, as potential methods to enhance immunotherapeutic outcomes. Understanding these mechanisms offers promising avenues for improving treatment efficacy and patient prognosis in TNBC.

Immune checkpoint blockade (ICB) has transformed cancer treatment, but success rates remain low in most cancers. Recent research suggest that dietary fiber enhances ICB response in melanoma patients and murine preclinical models through microbiome-dependent mechanisms. Yet, the robustness of this effect across cancer types and dietary contexts remains unclear. Specifically, prior literature compared grain-based chow (high fiber) to low-fiber purified diet, but these diets differ also on other dimensions including phytochemicals. Here we investigated, in mice fed grain-based chow or purified diets with differing quantities of isolated fibers (cellulose and inulin), metabolite levels and ICB activity in multiple tumor models. The blood and fecal metabolome were relatively similar between mice fed high- and low-fiber purified diets, but differed massively between mice fed purified diets or chow, identifying the factor as diet type, independent of fiber. Tumor growth studies in three implantable and two spontaneous genetically engineered tumor models revealed that fiber has a weaker impact on ICB (anti-PD-1) efficacy than previously reported. In some models, dietary modulation impacted ICB activity, but not in a consistent direction across models. In none of the models did we observe the pattern expected if fiber controlled ICB efficacy: strong efficacy in both chow and high-fiber purified diet but low efficacy in low-fiber purified diet. Thus, dietary fiber appears to have limited or inconsistent effect on ICB efficacy in mouse models, and other dietary factors that correlate with fiber intake may underlie the clinical correlations between fiber consumption and immunotherapy outcomes.

Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, aggressive progression, and resistance to conventional therapies. Despite advances in understanding its pathogenesis, including the identification of common genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) and dysregulated signaling pathways (e.g., KRAS-MAPK, PI3K-AKT, and TGF-β pathways), effective therapeutic strategies remain limited. Current treatment modalities including chemotherapy, targeted therapy, immunotherapy, radiotherapy, and emerging therapies such as antibody-drug conjugates (ADCs), chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), cancer vaccines, and bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these treatment approaches, emphasizing their mechanisms, limitations, and potential solutions, to overcome these bottlenecks. By integrating recent advancements and outlining critical challenges, this review aims to provide insights into future directions and guide the development of more effective treatment strategies for PC, with a specific focus on PDAC. Our work underscores the urgency of addressing the unmet needs in PDAC therapy and highlights promising areas for innovation in this field.

Cytotoxic T cell immune responses against cancer crucially depend on the ability of a subtype of professional antigen-presenting cells termed conventional type 1 dendritic cells (cDC1s) to cross-present antigens. Cross-presentation comprises redirection of exogenous antigens taken from other cells to the major histocompatibility complex class I antigen-presenting machinery. In addition, once activated and having sensed viral moieties or T helper cell cooperation via CD40-CD40L interactions, cDC1s provide key co-stimulatory ligands and cytokines to mount and sustain CD8+ T cell immune responses. This regulated process of cognate T cell activation is termed cross-priming. In cancer mouse models, CD8+ T cell cross-priming by cDC1s is crucial for the efficacy of most, if not all, immunotherapy strategies. In patients with cancer, the presence and abundance of cDC1s in the tumour microenvironment is markedly associated with the level of T cell infiltration and responsiveness to immune checkpoint inhibitors. Therapeutic strategies to increase the numbers of cDC1s using FMS-like tyrosine kinase 3 ligand (FLT3L) and/or their activation status show evidence of efficacy in cancer mouse models and are currently being tested in initial clinical trials with promising results so far.

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 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.

The gut microbiome has emerged as a potential factor in cancer pathogenesis, but its role in non-functioning pituitary neuroendocrine tumors (NF-PitNETs) remains unclear. This study aimed to elucidate gut microbiome and metabolomic alterations in NF-PitNETs by comparing microbial diversity, pathogenic bacteria, and serum metabolomic profiles between NF-PitNET patients and healthy controls. The gut microbiome was assessed through 16S rRNA sequencing, while serum metabolomics was analyzed using mass spectrometry. Correlation analyses identified potential links between microbial characteristics and metabolic markers. The results revealed that specific pathogenic bacteria, such as Bacteroides, were significantly enriched in NF-PitNET patients. Multi-omics correlations suggested that altered microbiota might contribute to NF-PitNET pathogenesis by modulating host metabolic pathways. These findings highlight the potential role of gut microbiome dysbiosis and its metabolic effects in NF-PitNET development, offering insights into possible therapeutic and diagnostic targets.