Targeting MD2 in prostate cancer bone metastasis: Mechanistic insights and therapeutic potential
Melina A. Dattilo1,2,*, Marina G. Ferrari3,*, Alexis P. Jimenez-Uribe4, Teresa Morales4, Kyle T. Amber5 and Adrian P. Mansini3,5
1 Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Buenos Aires, Argentina
2 CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
3 Department of Urology, Rush University Medical Center, Chicago, IL 60612, USA
4 Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612, USA
5 Department of Dermatology, Rush University Medical Center, Chicago, IL 60612, USA
Correspondence to:
Adrian P. Mansini, email: adrian_mansini@rush.edu
Keywords: prostate cancer; metastasis; MD2; biomarkers
Received: August 25, 2025 Accepted: March 04, 2026 Published: March 11, 2026
ABSTRACT
Metastatic prostate cancer (PCa), especially when it involves the bone, remains a significant clinical challenge with limited therapeutic options. Our recent research identified Myeloid Differentiation Protein-2 (MD2/LY96) as a potential biomarker associated with poor prognosis and higher metastatic potential in PCa. In this Research Perspective, we build on those findings and present new preclinical data showing that pharmacological inhibition of MD2 markedly reduces tumor growth in a PCa mouse model of bone metastasis. Analysis of patient tumor tissues demonstrated that high MD2 expression is associated not only with metastasis but also with increased infiltration of T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs), indicating a role in promoting an immunosuppressive environment. Additionally, we show that soluble MD2 (sMD2) may serve as a non-invasive biomarker of metastatic burden and help predict resistance to poly ADP-ribose polymerase (PARP) inhibitor therapy.
This Research Perspective aims to consolidate mechanistic and preclinical evidence supporting MD2 as a driver of prostate cancer metastasis and to evaluate the therapeutic potential of pharmacological MD2 inhibition in a bone metastasis model.
These findings support MD2 as a novel therapeutic target and identify soluble MD2 as a promising predictive and prognostic biomarker in metastatic PCa, with mechanistic links to immune evasion and inflammatory signaling.
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