Abstract Background Cancer cachexia (CC) is a systemic, metabolic wasting syndrome featuring body weight loss due to skeletal muscle and adipose tissue wasting. CC is suffered by ~80% of cancer patients that causes reduced performance status, intolerance to chemotherapy, and increased mortality. This debilitating condition is poorly understood and has no effective treatment. If CC therapy existed, it would improve treatment responses, increase quality of life, and prolong survival. With 50 years of study, the field has focused on defining pathways that promote atrophy in the end-organs most affected my cachexia. While this work has been fruitful, it has not led to identification of the upstream mediators of CC, nor has it generated effective therapies. There is an urgent need for high-quality discovery science and more detailed clinical phenotyping.We have created a virtual institute comprised of diverse, international, multidisciplinary scientists and clinicians with expertise in cancer, metabolism, neuroendocrine function, immunology, human metabolic diseases, preclinical models, and clinical phenotyping. We hypothesize that CC is driven by tumor-intrinsic factors that activate neurohormonal sickness pathways, which then induce anorexia, metabolic dysfunction, and tissue atrophy. Aims Project 1 - Identification of cancer-induced systemic metabolic dysregulation. Project 2 - Determination of tumor-immune drivers of cachexia. Project 3 - Defining the neuroendocrine response to cancer. Project 4 - Identification of clinical cachexia subtypes. Methods Our approach involves sophisticated measures of host-tumor interactions including innovative investigation of (1) systemic metabolic flux in mice using isotope tracing, imaging mass spectroscopy, dynamic nuclear imaging, and dietary and pharmacologic interventions; (2) cellular components and secreted factors from the tumor microenvironment using imaging mass cytometry, patient-derived organoid xenografts, microbial toxins, and CRISPR-based manipulations; (3) central pathways regulating appetite, behavior, and peripheral organ metabolism using human metabolic phenotyping, optogenetic, and pharmacological methods. We will perform the largest, most comprehensive observational study in CC subjects to thoroughly define CC subtypes and their clinical biomarkers using epidemiologic tools, novel image segmentation algorithms, and cluster analyses.