Adenosine phosphate signaling unleashes antitumor immunity and enhances immunotherapy efficacy in melanoma

Malignant melanoma, a highly aggressive skin cancer, remains a global health challenge due to its resistance to therapy and tumor microenvironment (TME) heterogeneity. In a landmark study, scientists from Central South University have decoded the role of adenosine phosphate signaling—mediated by purinergic P2 receptors (P2Rs)—in regulating TME dynamics and immunotherapy outcomes.

Key Findings: Signaling Subtypes and Prognostic Model

Using multi-omics analysis, the team identified five adenosine phosphate signaling subtypes in melanoma, categorized into two major metaprograms: metabolic and inflammatory. Subtype 5, characterized by high expression of P2RX1, P2RY12, and P2RY13, stood out for its strong association with immune activation, including inflammatory response, IFN-γ signaling, and antigen presentation.

The researchers developed the Adenosine Phosphate Signaling Model (APsig) to quantify this inflammatory subtype. In analyses of 1,068 tumor samples across nine public cohorts, high APsig levels were linked to longer overall survival (OS) and improved response to anti-PD-1/PD-L1 therapy. For example, in immunotherapy cohorts, high APsig patients showed a 30–50% higher response rate to checkpoint blockade compared to low APsig counterparts.

Mechanisms: Myeloid Cell Activation and Spatial Dynamics

Single-cell RNA sequencing (scRNA-seq) revealed that APsig is predominantly active in myeloid lineage cells (e.g., macrophages, dendritic cells), where it drives antigen presentation via MHC class I/II molecules. Spatial transcriptomics further showed that high APsig correlates with immune cell-rich niches at the tumor-stroma boundary, highlighting the importance of cellular crosstalk in immune surveillance .

Notably, APsig was negatively associated with immunosuppressive cell types (e.g., M2 macrophages, resting NK cells) and positively linked to cytotoxic T cell infiltration and T cell receptor (TCR) diversity, reinforcing its role in fostering a "hot" TME.

Therapeutic Implications

The study highlights APsig as a dual-purpose biomarker for both prognosis and immunotherapy prediction. Compared to traditional markers like TMB or PD-L1, APsig demonstrated comparable or superior accuracy in distinguishing responders to checkpoint therapy. Additionally, APsig may guide combination strategies, such as pairing immune checkpoint inhibitors with agents that enhance ATP signaling to further boost antitumor immunity.

Future Directions

While the study focuses on melanoma, the researchers suggest adenosine phosphate signaling may be relevant across solid tumors. Ongoing work aims to validate APsig in clinical trials and explore its utility in guiding personalized treatment regimens, including metabolic reprogramming and cell-based therapies.

See the Article:

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

https://doi.org/10.1002/mog2.70022