The therapeutic potential and mechanisms of action of the PROTAC molecule TSM-1 in STAT3-dependent epithelial cancers (HNSCC and CRC) were systematically assessed in vitro and in vivo, and especially with the patient-derived xenografts (PDX) and patient-derived organoids (PDO) during the discovery of PROTAC molecules, which further indicated that TSM-1, as the first PROTAC molecule, may serve as a promising proteolytic enhancer for STAT3-dependent epithelial cancer. The gene discussed is STAT3; the disease is head and neck squamous cell carcinoma.