Radiotherapy drives PD-1 expression on monocytes to attenuate anti-tumor immunity

Radiotherapy is a cornerstone of cancer treatment, but resistance in solid tumors frequently leads to treatment failure. The mechanisms underlying radiotherapy-induced resistance, particularly its immunomodulatory effects, remain unclear. This study demonstrates that radiotherapy upregulates PD-1 expression on tumor-associated monocytes via the adenosine-A2AR-cAMP-PKA-NF-κB pathway. These PD-1 + monocytes suppress the anti-tumor activity of CD8 + T cells. Targeting this subset enhanced radiotherapy efficacy. Notably, tissues from radiotherapy-resistant patients showed elevated infiltration of PD-1 + monocytes. Thus, we identify a distinct immunosuppressive monocyte subset that accumulates post-radiotherapy. Its depletion represents a promising strategy to overcome resistance and boost anti-tumor immunity.