Colorectal cancer (CRC) is strongly associated with obesity and type 2 diabetes (T2D), yet the mechanistic links between metabolic dysregulation, immune remodeling, and tumor progression remain unclear.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used to treat obesity and T2D, have been associated with reduced incidence of obesity-related cancers, including CRC, but the underlying mechanisms are unknown. This project aims to elucidate the immunometabolic interactions between obesity, diabetes, GLP-1 signaling, and colorectal carcinogenesis.

We will use an inducible colon-specific APC/KRAS genetically engineered mouse model combined with high-fat diet–induced obesity and insulin resistance, followed by GLP-1RA treatment, enabling distinction between systemic metabolic effects and tumor-driven immune changes. Immune profiling will be conducted in tumors and key metabolic organs (gut, visceral adipose tissue, spleen, mesenteric lymph nodes, liver) using flow cytometry and multiplex immunofluorescence, focusing on innate and adaptive immune populations, including NK cells, ?? T cells, myeloid cells, and B and T lymphocytes.

Tumor-intrinsic signaling pathways (Wnt/ß-catenin, MAPK, PI3K/AKT/mTOR, AMPK, STAT3) will be analyzed at the protein level to assess metabolic and oncogenic modulation. Translational validation will be performed using human FFPE CRC samples with clinical annotation of metabolic status and GLP-1 therapy, incorporating spatial immune profiling and mutational analysis. By integrating metabolic disease models, genetic cancer models, immune profiling, and pharmacological intervention, this project addresses a key gap in CRC research and may provide mechanistic insights with preventive and therapeutic relevance.