PML localization in tumor associated macrophages as a prognostic marker in triple negative breast cancer

Triple-negative breast cancer (TNBC) is a particularly aggressive and metastatic subtype, characterized by the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors. Outcomes for TNBC patients vary widely, suggesting this classification encompasses different cancers with distinct histological, genomic, and immunological profiles, leading to variable prognoses. The tumor microenvironment, particularly the expression and localization of promyelocytic leukemia protein (PML) in tumor-associated macrophages (TAMs), can influence patient outcomes by modulating inflammation. The beneficial prognostic role of increased tumor-infiltrating lymphocytes (TILs) in TNBC is well-established. In this retrospective study, we found that PML expression in tumor cells is inversely related to the presence of TILs and is associated with poorer outcomes. Patients with disease recurrence exhibited higher levels of TAMs with predominantly nuclear-localized PML, in contrast to patients who showed complete recovery. The accumulation of PML in the nucleus reduces its presence at ER-mitochondria contact sites, impairing its interaction with the NLRP3 inflammasome and leading to increased IL-1β secretion. This promotes a pro-inflammatory tumor microenvironment as seen in patients with adverse outcomes. Our findings suggest that both PML expression in cancer cells and its localization in TAMs can serve as additional prognostic factors, highlighting the potential of PML as a therapeutic target in TNBC.