For most patients with cancer, immune evasion and therapy resistance to immune checkpoint blockade are still a major concern, enabling tumours to grow unchecked. By contrast, a successful pregnancy requires the immune system to be dampened to avoid rejecting a growing fetus. This makes pregnancy an ideal physiological model to study overlapping immune tolerance mechanisms. Yu et al. compared active regulatory pathways in the tumour microenvironment (TME) of various cancers and the placenta, which revealed B7-H4 as a shared onco-fetal immune tolerance checkpoint.

In mouse models and cell lines of breast and gynaecological cancers, the authors were able to establish that progesterone signals are the main driver of B7-H4 expression via the progesterone receptor–P300–BRD4 axis. Whereas androgen has previously been linked to immune suppression in prostate cancer, this is the first time the sex hormone progesterone has been shown to affect immune response in cancer. Furthermore, inhibiting progesterone signalling in mice models of breast cancer and in patient-derived breast cancer tissues samples via a progesterone receptor antagonist or selective BRD4 degrader slowed cancer growth in mice and activated an immune response in B7-H4+ tumours.