Myeloid PTEN loss affects therapeutic response by promoting stress granules assembly and impairing phagocytosis of macrophages in breast cancer

Abstract

Abstract Breast cancer (BRCA) has become the most common type of cancer in women. The improvement of therapeutic response remains a challenge. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a classic tumor suppressor with emerging new functions discovered in recent years, and myeloid PTEN loss has been reported to impair the anti-tumor immunity. In this study, we revealed a novel mechanism of myeloid PTEN potentially affecting anti-tumor immunity in BRCA. We identified accelerated stress granules (SGs) assembly under oxidative stress in PTEN deficient bone marrow-derived macrophages (BMDMs), due to the upregulation of EGR1 transcripting TIAL1. The activation of PI3K/AKT/mTOR (PAM) pathway also contributed to the promoted SGs formation. ATP consumption during SGs assembly in BMDMs impaired the phagocytosis of 4T1 cells, which might contribute to the damage of anti-tumor immunity. In BRCA neoadjuvant cohort, we observed poorer response in myeloid PTENlow patients with G3BP1 aggregating as SGs in CD68+ cells, which was consistent with the mechanism that PTEN deficient macrophages tend to have easier SGs assembly with impaired phagocytosis in our study. Our results revealed an unconventional impact of SGs on BMDMs and might provided new perspectives for drug resistance and therapeutic strategies for BRCA patients.