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

Triple-negative breast cancer (TNBC) patients often develop resistance to Trop2 antibody-drug conjugate (ADC), and plasmacytoid dendritic cell (pDC) dysfunction is associated with poor prognosis in TNBC, but the underlying mechanism linking these two phenomena remains unclear.

The immune cell infiltration and prognosis of TNBC were analyzed through the TIMER database. Sacituzumab Govitecan (SG)-resistant MDA-MB231 cells and xenograft tumor models were established, and the function of pDC was regulated with CpG or anti-BDCA-2. The relationship between Protein arginine methyltransferase 5 (PRMT5) and immune cell infiltration was predicted by the Xiantao academic analysis. CCK-8, plate cloning, EdU and other experiments were used to detect cell functions. The functions of pDC were detected by flow cytometry and ELISA experiments. Besides, IP and IB experiments were implemented to detect the ubiquitination level of interferon regulatory factor 3 (IRF3) and the methylation level of midline 2 (MID2), and the protein interactions were verified through the Co-IP experiment.

TNBC tissues resistant to SG showed reduced pDC infiltration and impaired function, associated with downregulation of IRF3. PRMT5 was highly expressed in the cytoplasm of SG-resistant TNBC cells and negatively correlated with pDC cell infiltration. PRMT5 promoted MID2 methylation to induce the ubiquitination and degradation of IRF3. Moreover, silencing PRMT5 activated pDCs, reversed CD8⁺ T cell suppression, and enhanced the sensitivity of drug-resistant TNBC cells to SG in vitro and in vivo.

Targeting PRMT5 reshapes the immune microenvironment by restoring pDC function via the MID2-IRF3 axis, providing a promising strategy to reverse SG resistance in TNBC.