Targeting UPR Stress Signaling Pathways in PMN-MDSC to Overcome Therapy Resistance in Prostate Cancer

Polymorphonuclear Myeloid-Derived Suppressor Cells (PMN-MDSCs), also known as immune suppressive neutrophils, are critical drivers of prostate cancer (PCa) progression and therapy resistance. Although morphologically similar to classical neutrophils, PMN-MDSCs become pathologically activated in the tumor microenvironment (TME), suppressing antitumor immunity and promoting disease progression. They contribute to castration-resistant prostate cancer (CRPC) through the secretion of factors such as interleukin-23 and coagulation factor X (F10), which support androgen-independent tumor growth. While CXCR2-mediated infiltration of PMN-MDSCs can be targeted with inhibitors to improve therapy outcomes, we recently identified a CXCR2 low subset that persists in CRPC and exhibits a gene signature associated with immaturity and proliferation. Preliminary single-cell RNA sequencing from mouse PCa tumors further revealed that these immature PMN-MDSCs are enriched for unfolded protein response (UPR) pathways, indicating a dependence on endoplasmic reticulum (ER) stress signaling for survival and immunosuppressive function. However, whether the UPR dependency identified in mice translates to human CRPC remains unknown, representing a critical gap in our understanding of PMN-MDSC–driven CRPC in patients. This project aims to comprehensively characterize the heterogeneity of PMN-MDSCs in human PCa, define the role of UPR pathways in immature versus mature subsets, and evaluate the pharmacological inhibition of specific UPR signaling pathways to eliminate immature PMN-MDSCs subset.