We recently reported that HDAC6 is involved in the regulation of a number of immunosuppressive checkpoint proteins, including the Program Death Receptor Ligand 1 (PD-L1). This protein is one of the natural ligands for the PD-1 receptor present on T-cells, consistently reported to suppress T-cell activation, proliferation, and induce T-cell exhaustion, anergy and apoptosis. As a result, increased PD-L1 expression by cancer cells remains a fundamental escape mechanism from host immunity within the tumor microenvironment, and the understanding the molecular mechanisms modulating PD-L1 and other immunosuppressive mediators could lead to improved treatments for cancer patients. Several publications have linked the over-expression of PD-L1 in tumors and tumor microenvironment with a poor prognosis in several malignancies, including melanoma, ovarian, gastric and breast cancer, among many others. However, more detailed mechanistic information regarding the molecular events involved in the regulation of PD-L1 is still missing. Moreover, limited information is available about the participation of preclinical and clinical anti-cancer agents in the regulation of PD-L1 and other immunomodulatory pathways. As a result, this gap in knowledge is preventing the design of new immunotherapeutic combination therapies. Given the fact that HDAC6 is a potential regulator of immunosuppressive mediators, it opens up a new avenue for immunotherapy. By using selective HDAC6inh as adjuvants to ongoing immune blockade based treatments, we are aiming to further augment anti-tumor immune responses.