Tetrastigma Hemsleyanum Polysaccharide Suppresses Triple‐Negative Breast Cancer by Disrupting the Hippo‐YAP/TEAD4‐PDIA4 Axis and Endoplasmic Reticulum Stress Adaptation

ABSTRACT Triple‐negative breast cancer (TNBC) exhibits addiction to chronic endoplasmic reticulum (ER) stress, which sustains an aggressive metastatic phenotype through activation of the unfolded protein response (UPR). Here, we identify a previously unrecognized “ER‐stress addiction” axis in which the Hippo pathway effector TEAD4 directly transcriptionally upregulates the ER chaperone PDIA4. We further demonstrate that this axis can be pharmacologically targeted by a natural polysaccharide. Tetrastigma hemsleyanum polysaccharide (THP) selectively activates the Hippo kinase cascade, leading to YAP phosphorylation, cytoplasmic sequestration, and subsequent degradation. This cascade attenuates YAP/TEAD4 interaction and abolishes TEAD4 DNA‐binding activity. Moreover, THP downregulates TEAD4 expression. These combined effects drive transcriptional suppression of PDIA4, catastrophic disruption of ER proteostasis, and ultimately lethal ER stress in TNBC cells. Functionally, THP inhibits migration, invasion, angiogenesis, and intracellular Ca 2 + flux in vitro, and—importantly—blocks metastasis in patient‐derived organoids, zebrafish xenografts, and two syngeneic mouse models at non‐toxic doses. Multi‐omics analyses and rescue assays confirm the TEAD4‐PDIA4 axis as the core functional module. Our findings establish THP as a first‐in‐class, natural‐product‐based therapeutic that disrupts ER‐stress addiction in metastatic TNBC by targeting the Hippo‐YAP/TEAD4‐PDIA4 axis.