{"doi":"10.1158/2159-8290.cd-25-1212","title":"p21-Positive Senescent Stromal Cells Promote Prostate Cancer Immune Suppression and Progression That Can Be Reversed by Senolytic Therapy","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 that p16 and p21 mark distinct epithelial and stromal senescent populations, with p21+ nontumor 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 antitumor CD8+ T-cell immunity and inhibiting prostate tumor progression in mice. Suppression of BCL-xL or p21 also potentiated anti-PD-1 immune checkpoint blockade (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 antitumor immunity and enhancing immunotherapy outcomes. SIGNIFICANCE: Senescent cells accumulate in the tumor and stroma throughout prostate cancer progression and are associated with immune suppression in patients and mice. Senolytic strategies to clear p21+ senescent stromal cells can prevent prostate cancer progression and reactive cytotoxic T-cell immunity to potentiate anti-PD-1 ICB in advanced disease.","journal":"Cancer Discovery","year":2025,"id":514994,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9429,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":985856,"name":"Kelly D. 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