Cellular senescence can exert dual effects in tumors, either suppressing or promoting tumor progression. The senescence-associated secretory phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, favoring tumor-suppressive SASP factors over tumor-promoting ones. Here, we identify the retinoic-acid-receptor (RAR) agonist adapalene as an effective pro-senescence compound in prostate cancer (PCa). Reactivation of RARs triggers a robust senescence response and a tumor-suppressive SASP. In preclinical mouse models of PCa, the combination of adapalene and docetaxel promotes a tumor-suppressive SASP that enhances natural killer (NK) cell-mediated tumor clearance more effectively than either agent alone. This approach increases the efficacy of the allogenic infusion of human NK cells in mice injected with human PCa cells, suggesting an alternative therapeutic strategy to stimulate the anti-tumor immune response in "immunologically cold" tumors.

细胞衰老可以在肿瘤中发挥双重作用，抑制或促进肿瘤进展。衰老细胞释放的衰老相关分泌表型（SASP）在这种二分法中起着至关重要的作用。因此，临床挑战在于开发安全增强癌症衰老的疗法，有利于肿瘤抑制 SASP 因子而不是促肿瘤因子。在这里，我们确定视黄酸受体（RAR）激动剂阿达帕林是前列腺癌（PCa）中有效的促衰老化合物。 RAR 的重新激活会引发强烈的衰老反应和肿瘤抑制 SASP。在 PCa 的临床前小鼠模型中，阿达帕林和多西紫杉醇的组合可促进肿瘤抑制 SASP，与单独使用任一药物相比，该组合更有效地增强自然杀伤 (NK) 细胞介导的肿瘤清除。这种方法提高了注射人 PCa 细胞的小鼠同种异体输注人 NK 细胞的功效，提出了一种刺激“免疫冷”肿瘤中抗肿瘤免疫反应的替代治疗策略。