Thalidezine triggers Cathepsin B-mediated cell death in T-cell lymphoma by disrupting lysosomal function.

T-cell lymphoma (TCL) is an aggressive malignancy defined by poor prognosis and therapeutic resistance, demanding innovative strategies. Targeting the lysosome to induce cell death has emerged as a powerful anti-cancer strategy, however its potential as a therapeutic target in TCL is yet to be fully developed. Here we report that Thalidezine (Tha) is a new and highly selective lysosomotropic agent (LA) with strong activity against TCL. Thalidezine diminished the acidic pH, and more importantly, induced the lysosomal membrane permeabilization (LMP). This LMP was not a passive event; it triggered the immediate and critical release of the protease Cathepsin B (CTSB) from the lysosomal lumen. We demonstrate that this cytosolic CTSB is the key executioner, directly initiating the apoptotic cascade through caspase-3 activation. Remarkably, CTSB knockdown rescued TCL cells from Tha-induced death, confirming that the CTSB-caspase axis constitutes the major death axis. Furthermore, Tha demonstrated significant in vivo efficacy in TCL cells-bearing NOD/SCID mice. In conclusion our results reveal Tha is a novel potent drug candidate and uncover a defined mechanism by weaponizing lysosomes to release CTSB, thereby establishing a therapeutically relevant vulnerability in TCL.