Coixenolide Enhances Antitumor Immunity of Cytotoxic CD8 + T Cells by Inhibiting S100A8/A9‐CD36 Axis in Obesity‐Associated Pancreatic Adenocarcinoma

ABSTRACT Pancreatic adenocarcinoma (PAAD), characterized by an immunosuppressive tumor microenvironment (TME) and resistance to immunotherapy, exhibits a dismal prognosis further exacerbated by obesity. This study demonstrates the potent immunomodulatory and antitumor effects of coixenolide, a bioactive fatty acid ester from Coix lacryma‐jobi L., particularly in obesity‐associated PAAD. Utilizing high‐fat diet (HFD)‐fed mouse models, we found that coixenolide significantly inhibited tumor growth in HFD mice compared to control diet (CD) mice, correlating with enhanced intra‐tumoral CD8 + T cell infiltration and cytotoxicity, reduced regulatory T cells (Tregs), and increased tumor cell apoptosis. Single‐cell RNA sequencing (scRNA‐seq) of PAAD tissues revealed that coixenolide specifically expanded and activated cytotoxic CD8 + T cells within the TME of HFD mice. Further analysis identified distinct malignant epithelial cell clusters enriched in HFD tumors, characterized by high expression of S100a8/a9 and stemness potential. Coixenolide treatment significantly reduced these S100a8/a9 ‐expressing tumor cell populations and suppressed S100a8/a9 protein expression and secretion. Cell–cell communication analysis and functional assays revealed that tumor cell‐derived S100a8/a9 interacted with Cd36 on CD8 + T cells. This interaction promoted CD36‐mediated fatty acid uptake, leading to lipid peroxidation, ferroptosis, and functional exhaustion of CD8 + T cells. Coixenolide disrupted this axis by inhibiting tumor cell S100a8/a9 , thereby downregulating CD36 on CD8 + T cells, reducing lipid peroxidation and ferroptosis, and restoring CD8 + T cell cytotoxicity. Genetic knockout ( S100a9 KO) of tumor cells mimicked coixenolide's effects, enhancing CD8 + T cell function and suppressing tumor growth in vivo, especially in HFD mice. Clinical data confirmed elevated S100A8/A9 expression in human PAAD tumors correlated with poor survival, advanced stage, and higher histological grade, and scRNA‐seq of patient samples showed S100A8/A9 expression in malignant ductal cells. Collectively, these results identify coixenolide as an immune‐metabolic modulator that attenuates obesity‐driven immunosuppression in PAAD at least in significant part through inhibition of the S100A8/A9‐CD36 axis, with lipid peroxidation and ferroptosis of CD8 + T cells reduced. Other mechanisms potentially involving regulatory T cells warrant further investigation in the future. These findings suggest S100A8/A9‐CD36‐mediated intercellular crosstalk as a therapeutically actionable immune‐metabolic vulnerability in obesity‐associated PAAD.