CD73 on cancer-associated fibroblasts enhanced by the A(2B)-mediated feedforward circuit enforces an immune checkpoint

CD73, an ecto-5′-nucleotidase (NT5E), serves as an immune checkpoint by generating adenosine (ADO), which suppresses immune activation through the A(2A) receptor. Elevated CD73 levels in tumor tissues correlate with poor clinical outcomes. However, the crucial source of CD73 activity within the tumor microenvironment remains unspecified. Here, we demonstrate that cancer-associated fibroblasts (CAFs) constitute the prominent CD73(hi) population in human colorectal cancers (CRCs) and two CD73(−) murine tumor models, including a modified CRC. Clinically, high CAF abundancy in CRC tissues correlates strongly with elevated CD73 activity and poor prognosis. Mechanistically, CAF-CD73 expression is enhanced via an ADO-A(2B) receptor-mediated feedforward circuit triggered by tumor cell death, which enforces the CD73-checkpoint. Simultaneous inhibition of A(2A) and A(2B) pathways with CD73-neutralization synergistically enhances antitumor immunity in CAF-rich tumors. Therefore, the strategic and effective targeting of both the A(2B)-mediated ADO-CAF-CD73 feedforward circuit and A(2A)-mediated immune suppression is crucial for improving therapeutic outcomes.