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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\u2013PD-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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>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\u2013PD-1 ICB in advanced disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-1212","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T21:02:42Z","timestamp":1761339762000},"page":"571-591","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["p21-Positive Senescent Stromal Cells Promote Prostate Cancer Immune Suppression and Progression That Can Be Reversed by Senolytic Therapy"],"prefix":"10.1158","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2581-4345","authenticated-orcid":false,"given":"Lin","family":"Zhou","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Massachusetts Chan Medical 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