Unmasking the expression of PD-L1 in Myeloid Derived Suppressor Cells: A case study in lung cancer to discover new drugs with specific on-target efficacy

• PD-L1 displays variation of spatial conformation in response to phorbol ester stimulation, which may confer a critical enhancement in binding affinity. • PD-L1 conformational change may be associated with an immunoregulatory mechanism that affects therapies targeting the PD-1/PD-L1 checkpoint. • Eliminating MDSCs by promoting PD-L1 stabilized unfolded states on both PMN- and M-MDSCs could improve immunotherapy efficacy. • In view of these conformational properties, analysis of accumulation, expansion and survival of pathological immunosuppressive MDSCs could help to better understand and overcome the mechanisms of immunotherapy resistance, by developing new treatment strategies aimed at promoting PD-L1 stabilized unfolded states.