Pregnancy promotes tumor metastasis through adenosine-induced immunosuppressive neutrophils in pre-metastatic microenvironment.

Tumor metastasis is the primary cause of cancer treatment failure and mortality. Pregnant patients with cancer sometimes experience a poor prognosis and accelerated disease progression, yet the underlying mechanisms remain poorly understood. Here we show that pregnancy enhances tumor metastasis in female mice by elevating adenosine levels, which drives pre-metastatic niche remodeling. Myeloid cells in placental and uterine tissues exhibit increased expression of adenosine-generating enzymes, CD39 and CD73. The accumulated adenosine recruits neutrophils into the tissues of the pre-metastatic microenvironment and upregulates PD-L1 expression on these cells through the cAMP-PKA-NF-κB pathway, thereby suppressing CD8+ T cell function. Consistent with murine models, pregnant women exhibit elevated adenosine levels and increased PD-L1+ neutrophils in peripheral blood, hindering human T cell activation. Inhibiting the adenosine-PD-L1+ neutrophil axis reverses, at least partially, pregnancy-accelerated metastasis without affecting fetal development. These findings shed light on the mechanism of tumor metastasis mice during pregnancy and suggest potential therapeutic targets for treating cancers in pregnant patients.