The promyelocytic leukemia PML protein coordinates immune evasion in triple-negative breast cancer via independent and converging mechanisms

: Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options and high recurrence rates. Given the high immunogenicity of TNBC, immune checkpoint inhibitors have been recently incorporated into its treatment. However, immunotherapy extends survival in only a subset of patients, denoting an urgent need to better understand the regulatory mechanisms that shape TNBC-immune microenvironment interactions. In this study, we identified the promyelocytic leukemia PML protein as a new modulator of TNBC immunogenicity. By measuring transcriptional responses to PML perturbation in TNBC cells we found that PML supports chronic activation of inflammatory pathways, resulting in constitutive upregulation of immunosuppressive genes, including PD-L1. Accordingly, PML silencing in a TNBC mouse model led to a substantial reorganization of the tumor microenvironment, with accumulation of various T cell populations linked to immune activation and tumor rejection. Importantly, analysis of human TNBC datasets linked high PML levels to chronic expression of inflammatory gene sets and impaired immune activation in the tumor microenvironment. In parallel, mechanistic studies, including PML interactome mapping and genome-wide DNA methylation profiling, showed that PML cooperates with DNMT1 to repress HLA gene expression via CpG methylation, thereby impairing tumor recognition and T cell-mediated killing. In sum, this study identifies PML as a key mediator of immune evasion in TNBC by concomitantly fostering an immunosuppressive tumor microenvironment and suppressing antigen presentation and tumor recognition by T cells. As PML-targeting therapies are clinically available for leukemia patients, our findings position PML as a promising actionable target to enhance immune responses and improve outcomes for patients with TNBC.