Schematic representation of CLL-induced Rho GTPase signaling defects in T cells that suppress LFA-1 activation signaling and migration and how this is reversible with lenalidomide. Direct contact of CLL cells with T cells (immunosuppressive signaling) downregulates RhoA and Rac1 (positive regulators of LFA-1 activation, green) and potentiates Cdc42 activity (negatively regulates LFA-1 activation, blue) in T cells inducing an important signaling block that negatively regulates LFA-1 activity. This attenuated LFA-1 activating signaling model is supported by reduced expression and trafficking of Rap1 at the LFA-1–expressing membrane in CLL T cells. PIP5KC (phosphatidylinositol-4-phosphate 5-kinase type I γ) and PtdIns(4,5)P2 (phosphatidylinositol-4,5-bisphosphate) are critical for LFA-1 affinity modulation downstream of RhoA and Rac. Diminished Rho GTPase activity and cytoskeletal signaling would suppress subsequent outside-in signaling and LFA-1–mediated adhesion and migration on the CD54 ligand. The ability of lenalidomide (red) to restore normal T-cell Rho GTPase activity and LFA-1 activation provides, for the first time, an important molecular definition of its mechanism of action. Cereblon expression is required for this immunomodulatory activity of lenalidomide. Dotted lines indicate that it is yet to be determined if lenalidomide activates Rho GTPases directly or indirectly via the cereblon pathway. These results indicate that lenalidomide represents a powerful immunotherapy to rescue global T-cell motility defects in cancer patients.