Colorectal cancer (CRC) is the third most diagnosed malignancy worldwide, with its incidence predicted to rise by 60% to 2.2 million new cases annually by 2030. While other cancer treatments have advanced, no new therapies have emerged for 95% of CRCs over the past 15 years. However, recent biological insights from mouse and human models have identified a novel tumor cell state resembling a fetal-like response to colonic injury, driven by TNFα/STAT3. This state is found in about 80% of tumors, particularly during tumor evolution and metastasis, and represents new therapeutic opportunities. This project aims to accelerate drug development by targeting these tumor states. By removing supportive fibroblasts and reversing immunosuppression, fetal-like cells can potentially be re-polarized to enhance their response to immunotherapy. Our approach includes developing a platform for streamlined preclinical and clinical testing, using specialized mouse and human tissue cultures and medium throughput screening. The consortium will 1) reposition existing prioritized drugs, 2) identify surface molecules for targeted delivery, and 3) discover novel targets in synthetic lethal combinations. Our project uniquely combines advanced tools and human samples aligned with transgenic mouse models for in vivo interventions. We aim to 1) design novel complex models for drug and target screening, 2) improve readouts beyond viability, 3) develop combination therapies to enhance immunotherapy, and 4) identify tumor-specific surface markers for targeted treatments. This will create a comprehensive data and tool package to 1) reposition existing drugs for CRC, 2) design and test new compounds, and 3) develop companion diagnostics, facilitated by bilateral R&D, fee-for-service, and asset licensing.