Chemical Probes Reveal Interferon-Driven Biomarkers of PRMT5 Inhibitor Sensitivity and Guide Synergistic Therapy in Triple-Negative Breast Cancer

This study employed 10x Genomics single-cell RNA sequencing (scRNA-seq) technology to investigate the effects of the combination of the PRMT5 inhibitor LLY283 and the PARP inhibitor Olaparib, as well as the triple combination with PD-1 blockade, on the tumor microenvironment in a mouse model of triple-negative breast cancer (TNBC). Our research uncovers the regulatory effects of these drugs and their combinations on the tumor microenvironment, providing new strategies and insights for future clinical therapy. To establish a tumor-bearing mouse model, EMT6 cells (2×10^5) were subcutaneously injected into immunocompetent BALB/c mice. Once tumors became palpable, mice were randomized into groups and treated with LLY-283 (50 mg/kg, 3 days on/4 days off, purchased from MedChemExpress), anti-PD-1 antibody (200 μg every three days, purchased from BioCell), or Olaparib (50 mg/kg daily via intraperitoneal injection, purchased from MedChemExpress), as well as dual and triple combinations of these agents. After the treatment period, tumors were collected from the mice. Tumors free of necrosis and ulcers in the area from three mice were pooled together as one sample. Tumors were dissociated into single-cell suspensions for subsequent sequencing analysis.