Targeting PRMT5 to reshape the immune microenvironment and reverse Trop2 ADC resistance in triple-negative breast cancer.
5 affiliations
- 1Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, No. 127, Changle West Road, Xi'an, 710032, China.
- 2Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
- 3Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, No. 127, Changle West Road, Xi'an, 710032, China. [email protected].
- 4Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, No. 127, Changle West Road, Xi'an, 710032, China. [email protected].
- 5Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, No. 127, Changle West Road, Xi'an, 710032, China. [email protected].
Abstract
Background
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.Methods
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.Results
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.Conclusion
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.
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BibTeX
@article{kong2026targeting,
title = {{Targeting PRMT5 to reshape the immune microenvironment and reverse Trop2 ADC resistance in triple-negative breast cancer.}},
author = {Jing Kong and Minghui Li and Yidi Wang and Mengxuan Li and Huimin Meng and Jiajun Ding and Jing Fan and Ting Wang},
journal = {Cellular oncology (Dordrecht, Netherlands)},
year = {2026},
month = aug,
doi = {10.1007/s13402-026-01269-4},
url = {https://europepmc.org/article/MED/42957907},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Targeting PRMT5 to reshape the immune microenvironment and reverse Trop2 ADC resistance in triple-negative breast cancer.
AU - Jing Kong
AU - Minghui Li
AU - Yidi Wang
AU - Mengxuan Li
AU - Huimin Meng
AU - Jiajun Ding
AU - Jing Fan
AU - Ting Wang
PY - 2026
DA - 2026/08/04
JO - Cellular oncology (Dordrecht, Netherlands)
DO - 10.1007/s13402-026-01269-4
UR - https://europepmc.org/article/MED/42957907
AB - Background 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.Methods 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.Results 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.Conclusion 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.
SN - 2211-3428
SN - 2211-3436
ER -