Prostaglandin promotes tumor growth via inhibiting tumor antigen presentation in triple-negative breast cancer

Hormones play important roles in various physiological and pathological activities of the human body. However, in triple-negative breast cancer (TNBC), the most intractable breast cancer subtype with limited therapeutic targets, what hormones exist and what role they play remained unclear. Here, using a large cohort of TNBC patients ( n = 360), we discovered that the relative abundance of prostaglandin and its receptor prostaglandin E receptor 1 (PTGER1) mRNA expression were both related to poor prognosis. Mechanistically, this was achieved by the prostaglandin-PTGER1-KLK5 axis in tumor cells, which could induce an immune-inhibitory microenvironment by inhibiting tumor antigen presentation. We also found that PTGER1 promotes KLK5 transcription through transcription factor JUN, and KLK5 suppresses MHC-I expression and thus promoting immune evasion. Moreover, using preclinical models, we proved that inhibition of KLK5 could augment the immunotherapy efficacy in treating TNBC. Collectively, our findings offer novel insights into hormones and TNBC microenvironment, which may provide novel therapeutic targets for treating TNBC.