DNA damage response as a driver of PD-L1 expression in cellular senescence: implications for immune evasion and immunosenescence
Year: 2026
Type: review
Abstract: Aging is accompanied by the progressive accumulation of senescent cells, which contribute to tissue dysfunction and chronic inflammation. These cells persist despite a pro-inflammatory profile that should, in principle, recruit immune cells for their clearance. We propose that this persistence is explained, at least in part, by PD-L1-mediated immune evasion driven by the DNA damage response (DDR). The aim of this Mini Review is to synthesize evidence linking DNA damage response signaling, initiated by diverse senescence-associated stressors, to PD-L1 upregulation and immune evasion in senescence. We discuss how DDR signaling drives PD-L1 expression through transcriptional mechanisms, namely, the cGAS-STING pathway and the ATM/ATR-STAT1/IRF1 axis, and through post-translational stabilization via p16-mediated inhibition of CDK4/6. This review also discusses the function of PD-L1 in the nucleus, where it interacts with cohesin-SA1 to maintain telomere cohesion. Finally, it highlights that DDR-driven PD-L1 upregulation establishes a self-reinforcing circuit: immune evasion allows senescent cells to accumulate, which exacerbates telomere dysfunction in neighboring cells and reinforces the senescent phenotype. This framework recasts senescence as an actively maintained immunoevasive condition and identifies the DDR-PD-L1 axis as a potential target for restoring immune clearance of senescent cells.
Authors: Yajun Wang, Ling Qin
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7222483503