Failure to benefit from PD-1/PD-L1 blockade might also be due to effector T-cell exhaustion, which further inspires the development of mAbs targeting costimulatory receptors (e.g., CD27, OX40, CD40, 4-1BB/CD137) [189,191,192,193] to work as agonists that might overcome the immunosuppressive DLBCL microenvironment, stimulating effector T-cells and regulating T-cell memory responses. This evidence concerns the gene CD40 and diffuse large B-cell lymphoma.