In addition to its universally known role in transferring genetic material, DNA nucleotides and nucleosides are regarded as the most ancient form of extracellular signaling molecules. This unique signaling pathway was first reported by Dr. Albert Szent‐Györgyi in 1937 and established by Dr. Geoffrey Burnstock in 1972, who coined the term “purinergic signaling.” The significance of purinergic signaling is now recognized in various cellular processes, including immune responses. With an increased understanding of how changes in immunity impact cancer progression, the groundbreaking successes of immunotherapies, and emerging challenges facing patients receiving these treatments, in this review we revisit the history of purinergic signaling, provide a comprehensive summary of its impact on immune cells, and discuss the therapeutic potential of targeting this pathway for cancer treatment.