We show that dual STAT3/5 degradation through small‐molecular covalent inhibitors is potent in vitro and ex vivo, but blocking of upstream kinase action, such as PAK kinase, is necessary in vivo and could represent a promising therapeutic strategy to eradicate malignant cells in L‐CTCL. This evidence concerns the gene STAT3 and primary cutaneous T-cell non-Hodgkin lymphoma.