The potential challenges and focuses of sEV PD-L1 research in the following aspects: (1) selective purification of PD-L1-positive sEVs with natural properties and functions; (2) heterogeneity of PD-L1-positive sEVs; (3) standardization of sEV PD-L1-based liquid biopsy; (4) novel cancer therapies based on sEV PD-L1. Here, CD274 is linked to cancer.