Activation of Adenosine Phosphate Signaling Promotes Antitumor Immunity in Tumor Microenvironment and Facilitate Immunotherapy

ABSTRACT Adenosine 5′‐triphosphate (ATP) plays a crucial role in intracellular energetic metabolism and functions as a signal transducer in shaping the tumor microenvironment (TME). However, the understanding of the biological functions of adenosine phosphate signaling and its clinical relevance remains limited. Here, we deciphered the multi‐omics dysregulation of 15 purinergic P2 receptors (P2Rs) and their clinical relevance. We revealed the presence of 5 ATP signaling subtypes in melanoma, with two distinct functional metaprograms—one metabolic and the other inflammatory. We developed an adenosine phosphate signaling model (APsig) that showed promising prognostic value in melanoma, as well as predictive efficacy of immunotherapy across 1068 tumor samples in 9 independent public cohorts. High APsig was associated with longer overall survival (OS) and improved response to tumor immunotherapy. Additionally, through single‐cell and spatial transcriptomic analysis, we explored how APsig promotes antitumor immunity by activating myeloid lineage cells for antigen presentation. Our comprehensive characterization of P2R‐mediated adenosine phosphate signaling at both bulk/single‐cell and spatial transcriptomic levels highlights its potential as a promising target for developing novel anticancer agents, particularly in combination with immune checkpoint inhibitors.