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

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

  • Cancer Discov. 2025 Oct 27. doi: 10.1158/2159-8290.CD-25-1212.
Lin Zhou 1,  Kelly D DeMarco 1,  Katherine C Murphy 1,  Zhenpeng Wu 2,  Jinping Li 2,  Calvin Johnson 1,  Bin Liu 3,  Hadiya K Giwa 3,  Boyang Ma 4,  Nikita Bhalerao 5,  Junhui Li 1,  Zhong Jiang 1,  Shi Bai 1,  Chaitanya N Parikh 3,  Tianyi Ye 1,  Karl Simin 1,  Lihua J Zhu 1,  Jason R Pitarresi 5,  Hong Wu 2,  Marcus Ruscetti 1
Affiliations

Affiliations

  • 1 University of Massachusetts Chan Medical School, Worcester, MA, United States.
  • 2 Peking University, Beijing, P.R.China, China.
  • 3 University of Massachusetts Chan Medical School, United States.
  • 4 Cancer Center, University of Massachusetts Chan Medical School, United States.
  • 5 University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States.
PMID: 41135083 DOI: 10.1158/2159-8290.CD-25-1212
Abstract

Cellular senescence is a well-established tumor-suppressive cell cycle arrest program. However, chronic inflammation through the senescence-associated secretory phenotype (SASP) can alternatively drive immune suppression and Cancer progression. Using prostate Cancer patient samples and murine models, we find p16+ and p21+ senescent cells accumulate throughout malignant progression and associate with immune suppression. Single cell Sequencing revealed p16 and p21 MARK distinct epithelial and stromal senescent populations, with p21+ non-tumor cells expressing the highest SASP. p21+ stromal cell removal blocked the SASP to reverse immune suppression and slow tumor growth. Senolytic Bcl-xL Inhibitor treatment could clear p21+ stromal senescent cells, reactivating anti-tumor CD8+ T cell immunity and inhibiting prostate tumor progression in mice. Suppression of Bcl-xL or p21 also potentiated anti-PD-1 ICB in preclinical prostate Cancer models. Our findings demonstrate that targeting p21+ senescent stromal populations can yield therapeutic benefits in advanced prostate Cancer through activating anti-tumor immunity and enhancing immunotherapy outcomes.

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