PARP 抑制剂与 CDK4/6 抑制剂联合调节 cGAS/STING 依赖的治疗诱导衰老，并在结直肠癌中为抗 PD-L1 治疗提供“双重打击”机会

Although PARP inhibitor (PARPi) has been proven to be a promising anticancer drug in cancer patients harboring BRCA1/2 mutation, it provides limited clinical benefit in colorectal cancer patients with a low prevalence of BRCA1/2 mutations. In our study, we found PARPi talazoparib significantly induced cellular senescence via inhibiting p53 ubiquitination and activating p21.

Furthermore, CDK4/6i palbociclib amplified this therapy-induced senescence (TIS) in vitro and in vivo.

Mechanistically, talazoparib and palbociclib combination induced senescence-associated secretory phenotype (SASP), and characterization of SASP components revealed type I interferon (IFN)-related mediators, which were amplified by cGAS/STING signaling.

More importantly, RNA sequencing data indicated that combination therapy activated T cell signatures and combination treatment transformed the tumor microenvironment (TME) into a more antitumor state with increased CD8 T cells and natural killer (NK) cells and decreased macrophages and granulocytic myeloid-derived suppressor cells (G-MDSCs).

Moreover, clearance of the TIS cells by αPD-L1 promoted survival in immunocompetent mouse colorectal cancer models. Collectively, we elucidated the synergistic antitumor and immunomodulatory mechanisms of the talazoparib-palbociclib combination.

Further combination with PD-L1 antibody might be a promising "one-two punch" therapeutic strategy for colorectal cancer patients.