CDK4/6抑制剂（CDKi）已经在激素受体阳性、HER2阴性转移性乳腺癌中改善了疾病控制，但大多数患者会出现进展性疾病。我们探究了CDK4/6抑制后宿主基质的细胞衰老是否影响CDKi耐药乳腺癌细胞的转移和生长，使用了可诱导性老化的p16-INK-ATTAC小鼠模型。预处理未接受治疗的小鼠的帕博西尼可增加CDKi耐药同种异基因乳腺癌细胞在肺部的种植，而通过减少宿主衰老细胞，可以逆转这种效应。来自非肿瘤小鼠的肺的RNA测序分析表明，帕博西尼下调了与免疫相关的基因集和白细胞迁移相关的基因表达。同步老化逆转了其中部分效应，包括TGF-β和衰老相关信号通路的富集。CIBERSORTx分析揭示帕博西尼改变了肺内巨噬细胞/单核细胞种群。值得注意的是，帕博西尼预处理小鼠的肺转移瘤细胞露出了衰老的内皮细胞。体外模型中帕博西尼处理的内皮细胞表现出典型的衰老特征，在上调与细胞衰老相关的分泌表型、白细胞迁移和TGF-β介导的旁分泌性细胞衰老相关基因的同时，在共培养中诱导了肿瘤细胞迁移和单核细胞跨内皮侵袭。这些研究揭示了帕博西尼诱导的基质细胞衰老如何影响肺转移，并描述了帕博西尼诱导的基因表达变化在正常肺和内皮细胞模型中所对应的肺部转移灶肿瘤微环境的变化。

CDK4/6 inhibitors (CDKi) have improved disease control in hormone-receptor-positive, HER2-negative metastatic breast cancer, but most patients develop progressive disease.We asked whether host stromal senescence after CDK4/6 inhibition affects metastatic seeding and growth of CDKi-resistant mammary cancer cells by using the p16-INK-ATTAC mouse model of inducible senolysis.Palbociclib pretreatment of naïve mice increased lung seeding of CDKi-resistant syngeneic mammary cancer cells, and this effect was reversed by depletion of host senescent cells. RNA sequencing analyses of lungs from non-tumor-bearing p16-INK-ATTAC mice identified that palbociclib downregulates immune-related gene sets and gene expression related to leukocyte migration. Concomitant senolysis reversed a portion of these effects, including pathway-level enrichment of TGF-β- and senescence-related signaling. CIBERSORTx analysis revealed that palbociclib alters intra-lung macrophage/monocyte populations. Notably, lung metastases from palbociclib-pretreated mice revealed senescent endothelial cells. Palbociclib-treated endothelial cells exhibit hallmark senescent features in vitro, upregulate genes involved with the senescence-associated secretory phenotype, leukocyte migration, and TGF-β-mediated paracrine senescence and induce tumor cell migration and monocyte trans-endothelial invasion in co-culture.These studies shed light on how stromal senescence induced by palbociclib affects lung metastasis, and they describe palbociclib-induced gene expression changes in the normal lung and endothelial cell models that correlate with changes in the tumor microenvironment in the lung metastatic niche.