Beyond its role in regulating multiple physiological functions that impact health, the intestinal metagenome is implicated in cancer initiation, progression and responses to therapies, even for extraintestinal neoplasia. Hence, there is an urgent need to fully identify and functionally characterize minimalist commensal ecosystems relevant to cancer, with reliable and robust methods, to validate cancerassociated gut microbiome fingerprints of high clinical relevance, and to develop diagnosis tools that will become part of the oncological arsenal for the optimization and personalization of therapy. Based on retro-and pro-spective studies, with large discovery and validation cohorts enrolling >9,000 cancer patients across 10 countries, ancillary to ongoing innovative clinical trials or FDA/EMA approvals across 4 frequent cancer types, ONCOBIOME will pursue the following aims: 1/ identify and validate core or cancer-specific Gut OncoMicrobiome Signatures (GOMS) associated with cancer occurrence, prognosis, response to, or progression on, therapy (polychemotherapy, immune checkpoint inhibitors, dendritic cell vaccines) or adverse effects, 2/ decipher the functional relevance of these cancer-associated gut commensal ecosystems in the regulation of host metabolism, immunity and oncogenesis, 3/ integrate these GOMS with other oncology hallmarks (clinics, genomics, immunomics, metabolomics) 4/ design optimal companion tests, based on those integrated signatures to predict cancer occurrence and progression. With high carat interdisciplinary experts, ONCOBIOME expects to validate cancer or therapy-specific Gut OncoMicrobiome Signatures (GOMS) across breast, colorectal, melanoma and lung cancers adjusting for covariates, to unravel the mode of action of these GOMS in innovative platforms, thus lending support to the design of cancer preventive campaigns using well characterized pre-and pro-biotics.