Heterogeneous tumors consisting of DR5 sensitive (A), partially sensitive (B) and potentially resistant (C) tumor cells. DR5 agonist activates cell death above tumor clearance threshold in sensitive cells. Activation of caspase-8 and caspase-3 inactivates proteasome function and stabilizes intracellular PD-L1. Activated ROCK1 potentially help mobilizes PD-L1 to membrane by some unknown mechanism, which is also released in ApoEVs from dying cells. These PD-L1 containing ApoEVs shuttles and transfer cargo PD-L1 to other heterogenous cell types in tumors (potentially DR5 resistant) to increase the overall basal pool of PD-L1 in tumors. At the same time, due to extrinsic DR5 agonist mediated cytotoxicity, tumor cells are eliminated to generate partial tumor clearance and break down. However, incoming immune effector cells including T-cells are exhausted in the tumors due to overactive PD-L1, thus, limiting their anti-tumor response. Co-targeting ROCK1-DR5 reduces ApoEVs stabilized PD-L1 pool in tumors, while anti-PD-L1-DR5 co-targeting reduces immunosuppressive function of both basal and ApoEVs stabilized PD-L1 in tumors. 