P21-positive senescent stromal cells promote prostate cancer immune suppression and progression that can be reversed by senolytic therapy.

This study investigates the role of cellular senescence in prostate cancer progression, focusing on p16+ and p21+ senescent cells.

The researchers found that these senescent populations accumulate during malignancy and contribute to immune suppression, particularly through the senescence-associated secretory phenotype (SASP).

Single-cell sequencing identified distinct epithelial and stromal senescent cells, with p21+ stromal cells exhibiting the highest SASP expression.

Key findings include:

• Targeted removal of p21+ stromal senescent cells, either genetically or via BCL-xL senolytic inhibitors, reduced SASP.
• This removal reactivated anti-tumor CD8+ T cells and slowed tumor growth in murine models.
• Inhibiting BCL-xL or p21 enhanced the efficacy of anti-PD-1 immune checkpoint blockade.

These findings suggest that selectively targeting p21+ stromal senescent cells may improve immune responses and therapeutic outcomes in advanced prostate cancer.