Estrogen receptor regulation of the immune microenvironment in breast cancer

Breast cancer (BCa) is the most common cancer in women and the estrogen receptor (ER)+ subtype is increasing in incidence. There are numerous therapy options available for patients that target the ER, however issues such as innate and acquired treatment resistance, and treatment related side effects justify research into alternative therapeutic options for these patients. Patients of many solid tumour types have benefitted from immunotherapy, however response rates have been generally low in ER+ BCa. We summarise the recent work assessing CDK4/6 inhibitors for ER+ BCa and how they have been shown to prime anti-tumour immune cells and achieve impressive results in preclinical models. A great example of how the immune system might be activated against ER+ BCa. We review the role of estrogen signalling in immune cells, and explore recent data highlighting the hormonal regulation of the immune microenvironment of normal breast, BCa and immune disorders. As recent data has indicated that macrophages are particularly susceptible to estrogen signalling, we highlight macrophage phagocytosis as a key potential target for priming the tumour immune microenvironment. We challenge the generally accepted paradigm that ER+ BCa are “immune-cold” – advocating instead for research into therapies that could be used in combination with targeted therapies and/or immune checkpoint blockade to achieve durable antitumour responses in ER+ BCa.