Editorial: Microbiota-immune interactions: a new frontier in cancer treatment optimization

metabolism, promotion of DNA disfunction and abnormal cell growth resulting in gynecological cancers. They highlight the potential of microbiome with the microbial signature as non-invasive biomarkers and potential intervention including pre-and pro-biotics, modification of the diet, and, when possible, microbiota transplantation.Similarly, the narrative review by Chen H. and co-authors highlights the impact of the microbiota-reproductive axis, including gut and vaginal microbes, in modulating progression and response to therapy of gynecological malignancies. The microbiome described as an endocrine organ, named "estrobolome", regulates the systemic recirculation of estrogens and shapes a hyperestrogenic microenvironment fueling hormone-dependent tumorigenesis. Moreover, the microbiota controls the balance between immunosurveillance and inflammation, sustaining the mucosal barrier integrity and favoring tolerance. On the contrary, dysbiosis triggers chronic inflammation driving immunosuppression. Moreover, pathobionts induce genotoxicity that generates genomic instability, a hallmarker of cancer. From a translational point of view, the Author also discuss the use of probiotics, fecal microbiota transplantation, and precision microbial therapies, as innovative approaches for diagnosis, prognosis, and cancer treatment.The manuscript by Dora et. al. investigates the role of the proteomes of urinary extracellular vesicles (EVs) derived from both host and microbios as non-invasive predicting biomarkers for progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) patients treated with anti-PD1 inhibitor. In detail, bacterial proteins in urine EVs correlate with gut microbial abundance and PFS, reveals immune-microbiota interactions with higher bacterial/host protein ratio that correlates to long PFS. The Authors integrated proteomic data with machine learning to identify predictive protein signatures that may inform personalized immunotherapy approaches. Preclinical and clinical studies linking gut microbiota composition to immune checkpoint blockade (ICB) outcome in NSCLC were outlined in the systematic review from Jin and colleagues. The authors identified enrichment of Actinobacteria, Bacteroidetes, and Verrucomicrobia phylum and higher microbial diversity are associated with better ICB efficacy and reduced immune-related adverse events. Species, including Bifidobacterium in mice enhancing ICB efficacy via improved antigen presentation, T-cell priming and migration. Microbiota altering treatments, including antibiotic or proton pump inhibitor exposure 1 month prior to ICB were found detrimental in majority of studies, while a smaller number of studies found probiotics and diet were associated with increased microbiota diversity and composition and ICB efficacy. Also investigating lung cancer, the clinical correlative study by Song et. al. evaluated the microbiota composition and faecal metabolites of 26 patients with extensive-stage small cell lung cancer (ES-SCLC) treated with combined chemotherapy and ICB. Separating responders/non-responders by progression free survival duration, the authors performed metagenome sequencing and metabolite quantification on stool collected before and during treatment, identifying numerous correlations between specific gut microbiota, metabolite production and response to treatment. While a limited cohort was analysed, the authors findings support the gut microbiome as a predictive biomarker for ES-SCLC patients treated with chemoimmunotherapy.The effect of the microbiota of the urinary tract and gut on the prognosis and immunotherapy response of patients with bladder, renal and prostate cancer was also investigated in a systematic review by Zou et. al. Importantly, they focused on the spatial localization of microbiome and how this influences the molecular mechanisms of anti-tumor immunity that reflects the therapy response. A better understanding of the role of microbiome will pave the view for new strategies of cancer prevention and therapeutic approaches.The research article by Tajpara and colleagues explores the oncogenic properties of microbes isolated from intraductal papillary mucinous neoplasms (IPMNs) patients. The Authors took advantages of pancreatic spheroid models to resemble the tumor microenvironment and demonstrated that patient-derived microbes are able to colonize healthy spheroids in oxygen level-dependent manner and induce double-stranded DNA damage in pancreatic spheroids. Notably, they showed that microbes are recognized and activated peripheral mucosalassociated invariant T (MAIT) cells via riboflavin-derived metabolite sensing with potential clinical implications in cancer management.The review from Yang and colleagues outlines the mechanism by which the gut microbiota shapes immune responses during hepatocellular carcinoma (HCC) development and treatment. The authors outline the bidirectional gut-liver axis and describe the microbial dysbiosis observed in patients with HCC. Key microbial metabolites, including endotoxins, secondary bile acids, short chain fatty acids and indoles and their contribution to the profoundly immunosuppressive tumour microenvironment of HCC are described, as is the opportunity of targeting the microbiome to improve ICB outcomes in HCC. Another interesting article review on interconnection between microbiota and HCC was presented by Chen P. and colleagues. In their work, they analyzed the role of modulation of the intestinal microbiota by probiotics and how this can affect the efficacy of cancer immunotherapies. Gut microbiota dysbiosis could play a central role in HCC by generating carcinogenic products, altering equilibrium with the immune system, and increasing intestinal barrier permeability. This study emphasizes and describes mechanisms exerted by probiotics in regulating metabolic processes, inflammation and immune responses that are relevant for boosting antitumor immune responses.The review from Tingting et. al. focuses on the role of the intratumoral microbiota in shaping the tumor immune microenvironment. The authors outline the key intratumoral bacterial and fungal species and cancers they are known to colonise; while also discussing how they alter the tumour immune environment to influence cancer progression. The authors summarize the bispecific role that intratumoral bacteria have been shown to play in both inhibiting, and enhancing the efficacy of different cancer therapies. The methodological challenges in studying intratumoral microbes are discussed, as is the clinical potential of the tumour microbiota as a method of cancer diagnosis and as a target to enhance responses to immunotherapy.The review from Pan and colleagues explores the involvement of the infection-microbiomeimmunity axis in the carcinogenesis of bladder cancer. The authors identify and discuss different urinary infectious agents in combination with immune dysfunction induced. Also, they illustrate how persistent inflammation, oxidative stress, and epithelial injury are able to contribute to urothelial carcinogenesis. At the same time, the authors analyze the phenomenon of senescence and its role in worsening microbial persistence and inhibition of the anti-tumor immune response. Finally, they discuss innovative microbiome-targeted and immunomodulatory strategies with the purpose to restoring microbial-immune equilibrium and improving therapeutic efficacy. Instead, Hirasawa and co-workers investigate the relationship between aging of gut microbiota and the efficacy of ICB, studying stool samples from 36 aged patients with various solid tumors before the start of immunotherapy. In literature, data from age-related changes in the gut microbiota of patients with cancer are largely unexplored. The analysis of gut microbial composition through next generation sequencing revealed that in patients aged ≥75 years the presence of Veillonella species significantly decreased, whereas Streptococcus species was relatively more abundant in the Age ≥75 group. However, this study still represents an observational study with a limited sample size and lacking mechanism of the relationship between aging and ICBs efficacy. Therefore, further studies with larger cohorts are needed.Eventually, the manuscript by Zhou et al. analyzed the relationship between gut fungal biomarkers and bacterial-fungal interactions in three cohorts of cutaneous melanoma (CM) patients. In this experimental work, the Authors employed metagenomic sequencing analysis of stool samples collected prior immunotherapy. Biomarkers and key bacterial-fungal interactions determination were originated via metagenomics, machine learning, and SHapley Additive exPlanations (SHAP) methodology. This work revealed changes in gut bacterial and fungal composition in CM responders. Of note, the bacterial-fungal interaction analysis revealed a positive correlation interaction between Akkermansia and Rutstroemia in all cohorts, which may feature a key element associated with immunotherapy response in CM patients.Overall, this Research Topic underscores the microbiota-immune axis as a new frontier in cancer research and treatment optimization. Integrating multi-omics approaches, including metagenomics, metabolomics, transcriptomics, will a powerful framework to decode the functional impact of the microbiota on antitumor immunity, paving the way for microbiomebased interventions and more personalized, effective therapeutic strategies to enhance the efficacy and durability of immunotherapy for patients with cancer.