Targeting protein arginine methyltransferase 5 (PRMT5) reshapes the tumor immune microenvironment and restores sensitivity to the Trop2-directed antibody-drug conjugate sacituzumab govitecan in preclinical models of triple-negative breast cancer, according to a study published in Cellular Oncology.

Triple-negative breast cancer patients often develop resistance to Trop2 antibody-drug conjugates. Although prior research linked plasmacytoid dendritic cell dysfunction to poor clinical prognosis in triple-negative breast cancer, the specific cellular and molecular mechanisms connecting impaired dendritic cell activity to antibody-drug conjugate resistance remained poorly understood.

To investigate immune dynamics in this malignancy, the investigators evaluated immune cell infiltration and clinical prognosis data across triple-negative breast cancer profiles using the TIMER database. Additionally, predictive bioinformatic analyses performed through Xiantao academic analysis evaluated the relationship between PRMT5 expression levels and the extent of immune cell infiltration within the tumor microenvironment.

The experimental design integrated both cell culture and animal systems, establishing sacituzumab govitecan-resistant MDA-MB231 cell lines and corresponding xenograft tumor models. CCK-8, plate cloning, EdU, and other experiments were used to detect cell functions. To examine plasmacytoid dendritic cell activity, the team utilized flow cytometry and enzyme-linked immunosorbent assays (ELISA), while modulating dendritic cell function directly using CpG oligonucleotides and anti-BDCA-2 antibodies.

Immunoprecipitation and immunoblotting experiments evaluated the ubiquitination status of interferon regulatory factor 3 (IRF3) and the methylation status of midline 2 (MID2). Furthermore, co-immunoprecipitation assays were implemented to verify the physical protein-protein interactions occurring between these regulatory factors.

The study found that triple-negative breast cancer tissues resistant to sacituzumab govitecan exhibited significantly reduced plasmacytoid dendritic cell infiltration and impaired immune function, which correlated with the downregulation of IRF3. PRMT5 was abundantly expressed in the cytoplasm of resistant cells and correlated negatively with dendritic cell infiltration. Mechanistically, PRMT5 enhanced the methylation of MID2, which subsequently promoted the ubiquitination and degradation of IRF3.

Genetic silencing of PRMT5 reversed these suppressive effects, successfully reactivating plasmacytoid dendritic cells, overcoming CD8+ T cell suppression, and restoring the therapeutic sensitivity of resistant cancer cells to sacituzumab govitecan both in vitro and in vivo. The authors concluded that targeting PRMT5 restores dendritic cell competence via the MID2-IRF3 axis, offering a promising strategy to counteract sacituzumab govitecan resistance in triple-negative breast cancer.

Subject of Research: PRMT5 inhibition and mechanisms of Trop2 antibody-drug conjugate resistance in triple-negative breast cancer

Article Title: Targeting PRMT5 to reshape the immune microenvironment and reverse Trop2 ADC resistance in triple-negative breast cancer

Article References: Kong, J., Li, M., Wang, Y., Li, M., Meng, H., Ding, J., Fan, J., & Wang, T. (2026). Targeting PRMT5 to reshape the immune microenvironment and reverse Trop2 ADC resistance in triple-negative breast cancer. Cellular Oncology, 49(6), Article 142. https://doi.org/10.1007/s13402-026-01269-4

Image Credits: AI Generated

DOI: 10.1007/s13402-026-01269-4

Keywords: triple-negative breast cancer, PRMT5, sacituzumab govitecan, Trop2 ADC, plasmacytoid dendritic cells, IRF3, MID2, tumor microenvironment, drug resistance, Targeting, reshape, immune