Only few patients respond to tumor treatment as desired. Treatment heavily relies on host tumor interactions, including exploiting the host immune response against the tumor. The underlying mechanisms of host tumor interaction are largely unknown, guidance on specific intervention is missing. To improve outcome, better understanding of tumor-host interaction is needed. Large numbers of molecular snapshots will provide increased phenotyping coverage and better represent tumor-host evolution over time. In an innovative approach, MULTIR aims at investigating not a single tumor entity, but at compiling data from skin, lung and bladder cancer (most drugs target specific molecular features, irrespective of the tumor origin) to identify with high power the critical elements in the tumor-host interaction responsible for therapy response. In a multi-disciplinary approach involving leading clinicians, immunologists, experts in omics, digital technologies, social sciences and patient representatives from 10 EU countries and beyond, and an extensive outreach plan to ensure rapid transfer of MULTIR output to society, MULTIR combines existing multi-layer (epidemiological, genetic, clinical, pathologic, imaging, molecular) data from major studies on these tumors, using AI-based approaches to unveil functional modules regulating tumor-host interactions followed by validation of findings in models and synthetic patients. Harmonization with major EU initiatives will maximize use of European resources. Impact on all scientific, technological and societal levels is expected, including increased understanding of tumor-host interactions, generation of a unique resource of harmonized data on three major cancer types available to the community in compliance to the legal and ethics framework, boost of drug discovery, and an AI-based predictor for treatment response. MULTIR outreach plan includes policymakers and regulators, to support prompt assessment and uptake into the health systems. This action is part of the Cancer Mission cluster of projects on “Understanding (tumour-host interactions)”.