Deciphering the Therapeutic and Preventive Potential of Dietary Tannins in Osteosarcoma: A Multi‐Omics Approach Targeting <scp>TGFA</scp> and Immune Microenvironment Remodeling

ABSTRACT Malignant tumors, including osteosarcoma (OS), are major non‐communicable chronic diseases driven by systemic inflammation and oxidative stress. While dietary tannins possess known antioxidant and anticancer properties, their precise regulatory mechanisms and therapeutic targets in OS remain largely unexplored. This study integrated multi‐omics datasets to systematically investigate the potential of dietary tannins in OS, utilizing a machine‐learning framework based on 10 algorithms to construct a tannin‐related risk (TRR) score. The TRR model demonstrated favorable prognostic performance in retrospective cohorts, with high‐TRR patients exhibiting poorer survival, enrichment of extracellular matrix remodeling pathways, and reduced CD8 + T‐cell infiltration. Furthermore, immunotherapy prediction tools suggested a lower likelihood of response to immune checkpoint blockade in the high‐TRR group. TGFA was identified as a core hub gene contributing to the high‐risk phenotype; single‐cell and spatial transcriptomic analyses revealed that TGFA‐high OS cells exhibit stem‐like features and enhanced microenvironmental communication. In vitro assays confirmed that TGFA knockdown suppresses OS cell proliferation and migration while increasing apoptosis, whereas TGFA overexpression promotes these malignant behaviors. By bridging dietary polyphenol research with oncogenic management, this study identifies the TGFA‐associated immune axis as a precise molecular roadmap for the structural modification of polyphenols and the design of target‐specific, tannin‐based functional foods for chronic disease intervention.