Losartan Enhances Radiosensitivity by Reversing Immunosuppressive Tumor Microenvironment Induced by Radiotherapy in TNBC

Triple-negative breast Cancer (TNBC) is the most aggressive subtype of breast Cancer, with limited therapeutic options. Radiotherapy (RT) is a cornerstone of TNBC treatment; however, preclinical studies suggest that RT may both stimulate and suppress immune responses within the tumor microenvironment (TME). While RT can enhance immune responses, it may also induce an immunosuppressive TME, contributing to radioresistance. The renin-angiotensin system (Ras) is also involved in the immunosuppressive TME and tumor radioresistance. Previous research showed blocker of angiotensin II receptor (AGTR1), losartan, as a Ras Inhibitor, could alleviate hypoxia, thereby enhancing RT efficacy. Our study shows that high levels of AGTR1 may confer a poor prognosis and radioresistance in TNBC, and innovatively demonstrates losartan could enhance the radiosensitivity of TNBC in an immune dependent way. Furthermore, we found losartan could inhibit tumor-associated macrophages (TAMs) polarizing towards M2 phenotype, impedes the immunosuppressive function of myeloid-derived suppressive cells (MDSCs) induced by RT, and ultimately up-regulates the number and function of tumor-infiltrating CD8⁺ T lymphocytes. Besides, RNA-seq data reveals losartan impedes JAK2/STAT1 signaling activation upon irradiation, suppresses the interferon-related DNA damage resistant signature (IRDS) expression and diminishes the immune suppressive factors PD-L1 and IDO induced by irradiation in TNBC cells. Collectively, in our study, we investigate the role of losartan in radiosensitization and demonstrate losartan could reverse the immunosuppressive TME induced by RT in TNBC, which suggests that losartan combined with RT may represent a promising strategy for the treatment of TNBC.