The effects of ibrutinib and venetoclax on CLL cells in different microenvironments. (A) The lymph node provides a favorable microenvironment for CLL cells in which they receive survival signals from various stromal cells and immune cells via cell-cell interactions and soluble factors. BCL-2 family proteins, such as MCL-1 and BCL-XL, are upregulated, conferring resistance to venetoclax. (B) Ibrutinib covalently binds and inactivates BTK, leading to inhibition of BCR signaling. In addition, ibrutinib reduces chemokine receptor CXCR4, causing CLL cells to be released in the PB and impeding their homing back to the lymph nodes. (C) In the PB, recently emigrated CLL cells lose the supportive microenvironment, have reduced BCL-XL expression, and become dependent on BCL-2 signaling. Venetoclax directly targets BCL-2 (red arrow), whereas ibrutinib indirectly inhibits MCL-1 prosurvival protein (red dashed arrow), causing apoptosis of CLL cells. CCL3/4/22, C-C motif chemokine ligands 3, 4, and 22; CXCL12/13, chemokine C-X-C motif ligands 12 and 13; CXCR4, C-X-C chemokine receptor type; FDC, follicular dendric cell; MSC, mesenchymal stem cell; NLC, nurse-like cell. Figure created with BioRender.com.