A glucocorticoid-FAS axis controls immune evasion during metastatic seeding

Metastasis is the major cause of death for patients with triple-negative breast cancer and other solid malignancies. Metastases arise from cancer cells that disseminate from the original tumour, survive systemic immune surveillance and colonize new organs¹. Little is known about how initial disseminated tumour cells (DTCs) overcome anti-tumour immunity after seeding a new organ. Here we use a visible antigen in a model of triple-negative breast cancer with cognate CD8⁺ T cells to study the mechanisms of immune evasion in early metastatic seeding. Analysis of surviving DTCs revealed glucocorticoid receptor (GR) activation as a key driver of resistance to both CD8⁺ T cells and natural killer cells. Niche profiling using an optimized labelling tool identified FAS-FASL as a key pan-cytotoxic pathway against DTCs, which is repressed by GR activation. Pharmacological inhibition of GR in combination with immunotherapy reduced metastatic burden and expanded lifespan in mice. Thus, we identified a mechanism of immune evasion that operates specifically in DTCs, illustrating the unique immune-cancer interactions at this stage in the metastatic cascade. Our findings suggest that there are therapeutic opportunities to eliminate DTCs, separately from treatments aimed at primary tumours, and GR inhibition is one promising target.