Pregnancy and cancer metastasis: a mechanism found in mice

Pregnancy and cancer metastasis were connected in mouse experiments through a molecule that normally helps restrain inflammation. During late gestation, circulating adenosine rose, while the lungs and liver became more permissive environments for incoming tumor cells.

This does not mean that pregnancy causes cancer or inevitably accelerates its spread in people. The study tested a possible biological mechanism primarily in mice. Its human component involved healthy pregnant women, not pregnant patients with cancer.

How pregnancy altered the metastatic route

The researchers used several tumor models, including breast cancer, pancreatic cancer and melanoma, in pregnant, pseudopregnant and unmated mice. Tumor cells were implanted under the skin to follow primary tumor growth and spontaneous dissemination, or injected into the bloodstream to test their ability to colonize the lungs.

Primary tumors grew faster in pregnant animals, and their lungs developed more metastases. The difference persisted when tumor cells were delivered intravenously. That distinction matters because it separates metastatic colonization from the size of the primary tumor: pregnancy appeared to alter the distant organs themselves, not merely increase the number of cancer cells released into circulation.

Metabolomic profiling pointed to adenosine. This small signaling molecule is produced during the breakdown of ATP and accumulates during tissue stress, low oxygen and injury. Its normal role includes limiting excessive inflammation. In cancer, however, the same anti-inflammatory signal can weaken immune surveillance.

The uterus and placenta of pregnant mice contained more myeloid cells carrying the enzymes CD39 and CD73. Working in sequence, these enzymes convert extracellular nucleotides into adenosine. Their expression in reproductive tissues was roughly two to three times higher than in the uterus of nonpregnant mice, and blood adenosine increased during late gestation.

How adenosine reprogrammed immune cells

Neutrophils emerged as the main intermediaries. These innate immune cells usually arrive rapidly at sites of infection or tissue damage. Under adenosine exposure, they accumulated in the lungs and liver before visible metastases appeared, helping create what is known as a pre-metastatic niche.

Adenosine engaged the A2A receptor on neutrophils and activated a cAMP-PKA-NF-κB signaling sequence. This increased the amount of PD-L1 on the cell surface. PD-L1 binds PD-1 on T cells and delivers an inhibitory signal. Neutrophils with high PD-L1 suppressed the proliferation of CD8+ T cells and reduced their production of antitumor cytokines.

The result was an immunologically quieter organ in which disseminated tumor cells had a better chance of surviving. The evidence went beyond association: depleting neutrophils or blocking PD-L1, CD73 or the A2A receptor reduced metastasis in pregnant mice. Some combinations produced larger effects than individual interventions.

The team also tested tasquinimod, which inhibits the S100A9-related pathway involved in neutrophil recruitment. It reduced lung metastases. These experiments do not establish a treatment for pregnant patients, however. Animal groups were small, generally ranging from four to sixteen mice, and neither human dosing nor clinical safety was addressed.

What the human samples showed

The human comparison included 30 healthy women at 28 weeks of gestation or later and 30 age-matched nonpregnant women. Pregnant participants had higher circulating adenosine and neutrophil levels, along with increased PD-L1 on neutrophils. In laboratory assays, PD-L1-high neutrophils more strongly inhibited T-cell activation, while PD-1 blockade restored the response only partially.

Those findings make the mouse mechanism biologically plausible in humans, but they do not demonstrate clinical relevance. No pregnant cancer patients were enrolled, metastatic outcomes were not measured, and the study did not test whether adenosine predicts disease progression. Contributions from hormones, monocytes, macrophages and other pregnancy-associated changes also remain possible.

The experimental model has further limitations. Daily adenosine injections generated brief peaks because the molecule has a half-life of only seconds; this does not fully reproduce the sustained, lower-level exposure expected during pregnancy. Antibodies targeting CD73, PD-L1 and neutrophils crossed the placenta. The researchers observed no obvious changes in litter size or offspring weight up to weaning, but they did not comprehensively examine fetal immune development or later health.

The study therefore identifies a mechanistic trade-off that may accompany pregnancy-related immune tolerance. A pathway that helps protect the fetus from excessive maternal immune attack may, under certain conditions, also make it easier for disseminated tumor cells to evade immune control. The evidence is strong across several mouse models and is supported by blood measurements from healthy pregnant women, but it is not yet proof of a metastatic mechanism in pregnant cancer patients.