These findings implicate HSA5/6 in CTCL biology, suggest a unique sensitivity of CTCL to proteasome inhibitors and isoform-selective HSPA5/6 inhibitors (JG-023), and connect Hsp70 and UPR signaling to the Th2-dominant immunosuppressive phenotype of CTCL. Here, HSPA5 is linked to primary cutaneous T-cell non-Hodgkin lymphoma.