In order to overcome some of the limits of PD-L1 IHC testing, such as tissue unavailability for molecular testing in up to 30% of NSCLC patients [45] and spatial/temporal heterogeneity of IHC expression [46], some studies evaluated soluble PD-L1 (sPD-L1) or PD-L1 expression in Circulating Tumor Cells (CTCs) as an alternative source for PD-L1 evaluation as well as a dynamic biomarker in patients treated with conventional treatments [47,48,49] and/or ICIs [50,51,52,53,54]. This evidence concerns the gene CD274 and neoplasm.