Lung cancer is the most common cancer worldwide. Despite recent therapeutic advances, including targeted therapies and immune checkpoint inhibitors, the disease progresses in almost all advanced lung cancers and in up to 50% of early-stage cancers. The purpose of this review is to discuss whether purinergic checkpoints (CD39, CD73, P2RX7, and ADORs), which shape the immune response in the tumor microenvironment, may represent novel therapeutic targets to combat progression of non-small cell lung cancer by enhancing the antitumor immune response.