How lenalidomide targets the CLL TME. In contrast to conventional targeted drugs, lenalidomide seems to exert most of its anti-CLL activity by interfering with protumoral TME interactions rather than directly targeting prosurvival signaling in the tumor clone itself. Recent MOA data have shown that the IMiD lenalidomide binds to the protein CRBN, which modulates its substrate recognition and augments the ubiquitylation and degradation of critical transcription factors in lymphocytes. Ikaros (IKZF1) and Aiolos (IKZF3) are the downregulated targets in MM that cause direct malignant B-cell toxicity. Whether these transcription factors are targeted by lenalidomide in the diverse cellular components of the CLL TME remains to be investigated. This IMiD retargeted CRBN-dependent ubiquitin ligase activity simultaneously alters malignant B-cell and nonmalignant T-cell function. (i) Emerging data have shown that a retargeted CRBN complex directly inhibits TME-mediated proliferation signaling in CLL B cells that is associated with reduced expression of IKZF1 and IKZF3 in common with myeloma. (ii) Importantly, degradation of Ikaros and Aiolos in T cells stimulates IL-2 secretion that enhances immune function. Lenalidomide has been shown to effectively reverse tumor-induced immune suppression/privilege. Immunomodulatory MOA includes: promoting a Th2 to Th1 CD4⁺ T-cell switch, downregulating immunosuppressive signaling axes (eg, PD:L1:PD1) while enhancing costimulatory molecules that positively regulate antitumor CD8⁺ T-cell function and the induction of humoral immunity (residual normal B cells). CRBN-dependent activation of RHO GTPase activation signaling and cytoskeletal signaling repairs T-cell lytic immune synapse and motility function. (iii) Lenalidomide also modulates tumor-educated stromal cells (TAMs/NLCs and MSCs) in the TME that block essential survival signals for the expanding malignant B-cell clone. MM, multiple myeloma.