PDPN (podoplanin) is a cell-surface mucin-like glycoprotein with multifaceted roles in cell migration, adhesion, and tumor progression. Mechanistically, PDPN mediates platelet activation through CLEC1B binding, a critical function in blood-lymphatic vessel separation 1. PDPN promotes epithelial-mesenchymal transition (EMT) via MSN/EZR interaction, triggering RHOA activation and increasing cell invasiveness 2. The protein controls invadopodia stability in tumor cells through RHOC/ROCK1/ROCK2 signaling, facilitating extracellular matrix degradation 1. Additionally, PDPN enhances directional migration through CD44 interaction and regulates lymph node fibroblastic reticular cell adhesion via ERM protein activation. Clinically, PDPN expression correlates with poor prognosis across multiple cancers. PDPN+ cancer-associated fibroblasts (CAFs) promote oral squamous cell carcinoma progression via exosomal lncRNA FTX transfer, inhibiting ferroptosis 3. In breast cancer, PDPN+ CAFs confer trastuzumab resistance by suppressing NK cell-mediated cytotoxicity through IDO1/TDO2 secretion 4. In colorectal cancer, PDPN+ CAFs maintain pro-angiogenic functions through PDPN/CCL2/STAT3 feedback loops 5. A novel PDPN antagonist peptide (CY12-RP2) effectively inhibits melanoma growth by blocking Wnt/β-catenin signaling and enhancing anti-tumor immunity 2. These findings establish PDPN as a promising therapeutic target in cancer treatment.