由于治疗诱导衰老 (TIS) 可以支持或抑制癌症进展，因此确定哪些类型的化疗药物可以产生最强的抗肿瘤 TIS 是一个重要问题。在此，将细胞周期蛋白依赖性激酶4/6 抑制剂 (CDK4/6i) 诱导的衰老与传统 DNA 损伤剂诱导的 TIS 进行了比较。尽管两种类型的药物都会引起相似程度的衰老，但我们观察到衰老相关分泌表型 (SASP) 和与促肿瘤免疫相关的配体 (IL6、CXCL8、TGFβ、CD274、CEACAM1) 和血管生成 (VEGFA) 的表达增加主要是由 DNA 损伤剂而不是 CDK4/6i 诱导的 TIS。此外，尽管所有药物均增加了与抗原呈递相关的抗肿瘤免疫调节蛋白（MHC-I、B2M）和 T 细胞趋化因子（CXCL9、10、11）的表达，但 CDK4/6i 诱导的衰老细胞仍将这种表达维持在尽管没有核因子-κ-B (NF-κB) 和 p53 激活，但与用 DNA 损伤剂处理的细胞相比，强度相似甚至更高。这些数据表明，与通过促炎 SASP 增强促肿瘤微环境的 DNA 损伤剂相比，CDK4/6i 只能与抗肿瘤免疫调节蛋白一起产生 TIS。本文受版权保护。版权所有。

Since therapy-induced senescence (TIS) can either support or inhibit cancer progression, identifying which types of chemotherapeutic agents can produce the strongest anti-tumor TIS is an important issue. Here, cyclin-dependent kinase4/6 inhibitors (CDK4/6i)-induced senescence was compared to the TIS induced by conventional DNA-damaging agents. Despite both types of agents eliciting a similar degree of senescence, we observed increased expression of the senescence-associated secretory phenotype (SASP) and ligands related to pro-tumor immunity (IL6, CXCL8, TGFβ, CD274, CEACAM1) and angiogenesis (VEGFA) mainly in TIS induced by DNA-damaging agents rather than by CDK4/6i. Additionally, although all agents increased the expression of anti-tumor immunomodulatory proteins related to antigen presentation (MHC-I, B2M) and T cell chemokines (CXCL9, 10, 11), CDK4/6i-induced senescent cells still maintained this expression at a similar or even higher intensity than cells treated with DNA-damaging agents, despite the absence of nuclear factor-kappa-B (NF-κB) and p53 activation. These data suggest that in contrast with DNA-damaging agents, which augment the pro-tumorigenic microenvironment via pro-inflammatory SASP, CDK4/6i can generate TIS only with antitumor immunomodulatory proteins.This article is protected by copyright. All rights reserved.