These findings delineate a novel acquired cancer resistance mechanism to anti-PD-L1: PD-L1 blockade induced TNFRSF14 elevation in malignant cells, which serves as the dominant IC mediating cancer intrinsic adaptative resistance to PD-L1 blockade and related IFN-γ elevation in GBM. Here, TNFRSF14 is linked to glioblastoma.