Triple negative breast cancer (TNBC) is an aggressive disease associated with poor prognosis. Several lines of evidence suggest that anti-tumour immunity can contribute to breast cancer control if appropriately activated. However, the current regimen of checkpoint immunotherapy only benefits a minority of breast cancer patients, suggesting the existence of immune evasion mechanisms beyond the PD1/CTLA4 axis.
Existing literature suggest cancer associated fibroblasts (CAF) actively impedes effective immune response in TNBC and this is predominantly driven by ACTA2+ CAF. Using high throughput compound screening, CAF-immune coculture and single-cell sequencing, we identified a novel hypoxia-inducible factor prolyl hydroxylase inhibitor capable of reprogramming ACTA2+high CAF into ACTA2+low CAF. Importantly, reprogrammed ACTA2+low CAF had reduced ability to suppress T cells and display a quiescent-like gene expression profile. Together, our results demonstrate that targeting ACTA2+ CAF can improve immune cells activity, leading to greater anti-tumour immunity.