Venetoclax treatment effectively reduces all CLL subpopulations; however, it simultaneously triggers a rapid upregulation of antiapoptotic proteins, including BCL-2, BCL-XL, and MCL-1, in the surviving cells, thereby diminishing their sensitivity to the drug. This upregulation of antiapoptotic proteins is dependent on a significant depletion of CLL cells and requires access to the B-cell cytokine BAFF. These findings suggest that the sensitivity of CLL cells to venetoclax is mediated by a cytokine-dependent mechanism, highlighting the importance of targeting cytokine signals to enhance therapeutic efficacy. Created with BioRender.com.