Model depicting PD-L1 regulation and mechanism of immune tolerance in DLBCL. In PD-L1⁺ B-cell lymphoma cells, BCR-mediated NFATc1 activation upregulates IL-10 chemokine expression. Released IL-10 activates the JAK2/STAT3 pathway, leading to STAT3-induced PD-L1 expression. IL-10 antagonist antibody abrogates IL-10/STAT3 signaling and PD-L1 protein expression. BCR pathway inhibition by BTK inhibitors (ibrutinib, acalabrutinib, and BGB-3111) blocks NFATc1 and STAT3 activation, resulting in inhibition of IL-10 and PD-L1 expression. Downregulation of IL-10/PD-L1 signaling could potentially release the immune tolerance brake, allowing anergic T cells to become activated CD8⁺ cytotoxic T cells and target and destroy tumor cells. This immune tolerance mechanism also could be controlled and regulated by the tumor microenvironment via tumor-associated macrophages that are recruited by the tumor cells through CCL3 and CXCL10 chemokines.