LncRNA PVT1 drives macrophage polarization and triple-negative breast cancer progression via PPARγ-mediated...

Triple-negative breast cancer (TNBC) is a clinically aggressive subtype with limited therapeutic strategies. Although long non-coding RNAs (lncRNAs) are increasingly linked to tumor progression, their regulatory role in macrophage polarization during TNBC remains unclear. This study investigates the molecular interplay between lncRNA PVT1 and PPARγ in driving macrophage reprogramming during TNBC progression. Utilizing an orthotopic TNBC mouse model, single-cell RNA sequencing (scRNA-seq) identified nine distinct cell types, with pseudotime trajectory analysis revealing macrophage accumulation in advanced tumor stages. Reannotation of macrophages highlighted M2-like polarization dominance during TNBC development. Bulk sequencing of TNBC macrophages and integrated GEO/TCGA analyses identified PPARγ as a key regulator and PVT1 as a differentially expressed lncRNA in TNBC versus normal tissues. In vitro experiments with THP-1/U937 macrophages demonstrated that PVT1 knockdown or PPARγ modulation altered macrophage polarization, subsequently affecting MDA-MB-231 and MCF-7 breast cancer cell proliferation and invasion. Mechanistically, RNA/DNA pulldown and luciferase assays confirmed that PVT1 recruits NOP56 and E2F1 to form a transcriptional complex, enhancing E2F1-driven PPARγ expression. In vivo, orthotopic tumors generated from PVT1-silenced THP-1/MDA-MB-231 cell mixtures exhibited suppressed growth, increased M1-like macrophages, and elevated apoptosis (TUNEL assay), whereas PPARγ overexpression accelerated tumor progression with M2-dominant infiltration (flow cytometry). These findings establish lncRNA PVT1 as a critical epigenetic scaffold coordinating NOP56-E2F1-PPARγ signaling to polarize macrophages toward a pro-tumorigenic M2 phenotype, thereby fueling TNBC aggressiveness. This study unveils novel therapeutic targets for TNBC by disrupting the PVT1-PPARγ axis to rebalance macrophage dynamics and induce tumor-suppressive immunity.