Putative mechanisms of immune checkpoint inhibitor–associated hematologic toxicities. Anti–CTLA-4 therapy blocks inhibitory signals to cytotoxic (CD8⁺) and helper (Th1 and Th2) T lymphocytes and suppresses the activation of Tregs (CD4⁺ and CD25⁺). (B) PD-1/PD-L1 therapies have identical effects plus they block inhibitory signals to B lymphocytes, NK cells, and macrophages. The direct effects on T-lymphocyte classes and subclasses unleash cytotoxicity. These effects plus the indirect (CTLA-4 inhibition unleashing Th2CD4⁺ lymphocytes) and direct (anti–PD-1 and anti–PD-L1) effect on B lymphocytes leads to autoantibody production. CD8⁺ T-lymphocyte cytotoxicity and B-cell synthesis of autoantibodies are putative mechanisms of ICI-associated anemia, thrombocytopenia, neutropenia, and bone marrow failure. PD-1 and PD-L1 blockers that unleash NK cells could also result in direct bone marrow cytotoxicity. The direct effect of PD-1 and PD-L1 blockers on macrophage activity and the indirect effect of CTLA-4 blockade on unleashing Th1CD4⁺ and CD8⁺ T lymphocytes to stimulate macrophages could result in excessive cytokine production allegedly mediating HLH (IL-6) and VTE (IL-8).