Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer

Area of Science:

• Biomedical Engineering
• Immunology
• Oncology
• Nanotechnology

Background:

• Fibrotic remodeling creates immune-suppressive microenvironments, impairing organ function and limiting cancer immunotherapy response.
• Cellular senescence drives fibrosis but is heterogeneous, with both beneficial and pathogenic roles, complicating targeted therapies.

Purpose of the Study:

• To identify specific markers on senescent cells driving fibrotic diseases and tumors.
• To develop a nanoparticle-based therapeutic strategy for selectively targeting pathogenic senescent cell subsets.

Main Methods:

• Identified P-selectin as a selective marker on senescent-like cells in fibrotic tissues and tumors.
• Developed fucoidan-based nanoparticles (senescence-modulating nanoparticles, SMNPs) targeting P-selectin.
• Investigated SMNP efficacy in modulating fibrotic microenvironments and immune responses in vivo.

Main Results:

• SMNPs selectively targeted P-selectin expressing senescent-like cells.
• SMNPs demonstrated potent antifibrotic and immunomodulatory effects, enhancing therapeutic index.
• Targeting pathogenic macrophages with SMNPs restored immune infiltration in fibrotic tumors, sensitizing them to immunotherapy.

Conclusions:

• P-selectin is a viable target for selectively modulating pathogenic senescent cells.
• SMNPs represent a generalizable nanotherapeutic strategy for treating fibrotic diseases and enhancing cancer immunotherapy.
• Targeting senescent cells via SMNPs offers a novel approach to overcoming immune suppression in cancer and fibrotic conditions.