LMP7-Specific Inhibitor M3258 Modulates the Tumor Microenvironment of Triple-Negative Breast Cancer and Inflammatory Breast Cancer

Authors

Xuemei Xie
Jangsoon Lee
Ganiraju C Manyam
Troy Pearson
Gina Walter-Bausch
Manja Friese-Hamim
Sheng Zhao
Julia Jabs
Angela A Manginelli
Nadine Piske
Thomas Mrowiec
Corinna M Wolf
Bharat S Kuntal
Debu Tripathy
Jing Wang
Michael P Sanderson
Naoto T Ueno

Language

English

Publication Date

6-4-2025

Journal

Cancers

DOI

10.3390/cancers17111887

PMID

40507366

PMCID

PMC12153562

PubMedCentral® Posted Date

6-4-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) are the most aggressive molecular subtypes of breast cancer. Poor clinical outcomes highlight the pressing need to discover novel targets for the effective treatment of these diseases. LMP7 (β5i/PSMB8), a proteolytic subunit of the immunoproteasome, is implicated in the pathogenesis of multiple myeloma, autoimmune and inflammatory diseases, and inflammation-related cancers. However, the role of LMP7 in TNBC and IBC remains poorly characterized. Here, we evaluated the function of LMP7 in TNBC and IBC using the selective LMP7 inhibitor M3258. In human TNBC patient samples, LMP7 expression correlated strongly with CD8+ T cell infiltration and activation markers. M3258 inhibited LMP7 activity, reduced viability, and induced apoptosis in TNBC/IBC cell lines in vitro. In a novel immunocompetent in vivo model of TNBC/IBC, M3258 reduced tumor growth and the tumor abundance of M2 macrophages. Additionally, M3258 activated tumor-infiltrating CD8+ T cells and suppressed the expression of specific inflammatory pathway gene signatures in immune cells. Co-culture with M2 macrophages enhanced the invasiveness of TNBC/IBC cells, which was effectively suppressed by M3258 treatment. Our results demonstrate for the first time that LMP7 shapes the pro-tumorigenic microenvironment of TNBC/IBC, in part by modulating the pathogenic role of M2 macrophages. These findings suggest that LMP7 may represent a novel target for therapeutic intervention in TNBC/IBC.

Keywords

IBC, LMP7, M3258, TNBC, tumor microenvironment

Published Open-Access

yes

Recommended Citation

Xie, Xuemei; Lee, Jangsoon; Manyam, Ganiraju C; et al., "LMP7-Specific Inhibitor M3258 Modulates the Tumor Microenvironment of Triple-Negative Breast Cancer and Inflammatory Breast Cancer" (2025). Faculty, Staff and Student Publications. 6644.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6644