Fig. 2

The mechanism by which DDR affects PD-L1 expression and TME in tumors. In tumors, the defectiveness or inhibition of the DDR can lead to the accumulation of DNA damage, whereby double-stranded DNA and single-stranded DNA both accumulate in cytoplasm. Cytoplasmic DNA activates the cGAS/STING and RIG-I/MAVS pathways and eventually the type I interferon (IFN) pathway, ultimately recruiting both chemokines and immune cells (such as T cells, NK cells, and DCs). Specifically, STING promotes the phosphorylation and nuclear translocation of type I IFN transcriptional regulatory factors TBK1 and IFN regulator 3 (IRF3), while also activating the NF-κB pathway that interacts with IRF3. RIG-I can be considered an important participant in the immune activation of cancers presenting with genomic instability, as it can be activated via DNA, and combined with the adapter molecule MAV, which then activates IKK and/or TBK1 when stimulated, and finally activates the type I IFN pathway through downstream transcription factors. The activated TIL releases IFNγ, which acts on tumor cells and mediates STAT1/3-dependent PD-L1 upregulation. The ATM/ATR/Chk1 pathway can also induce PD-L1 expression. ATM can directly activate and participate in STING-mediated downstream pathways, and PARPi can promote PD-L1 expression by downregulating GSK3β. The release of the HMGB1 protein from dying tumor cells can bind TLR-4 on the surface of both DCs and macrophages in order to induce INF-β (TRIF) signal transduction, which subsequently activates IRF3 and NF-κB pathways. In addition, TLR4 recruits MyD88 and activates the NF-κB pathway to promote the transcription and secretion of various pro-inflammatory factors. Following this sequence of events, these factors serve to promote DC activation and trigger an immune response. HMGB1 can also upregulate PD-L1 expression in adjacent surviving tumor cells via TLR4/MyD88/TRIF signaling. In addition, ATM inhibitors can inhibit the induction of Tregs by tumor cell-derived small extracellular vesicles (sEV). (ATM: Ataxia telangiectasia mutated protein; ATR: Ataxia telangiectasia and Rad3-related protein; CCL5: C-C motif chemokine ligand 5; cGAMP: Cyclic GMP-AMP; cGAS: Cyclic GMP-AMP synthase; CHK1: Checkpoint kinase 1; CTL: Cytotoxic CD8+ T cell; CXCL10: C-X-C motif chemokine ligand 10; DDR: DNA damage response; DNAM-1: DNAX accessory molecule 1; DSB: Double-strand break; GSK-3β: Glycogen synthase kinase-3β; HMGB1: High mobility group box 1; IFNγ: Interferon-γ; IFNGR: Interferon gamma receptor; IKK: IκB kinase; IRF1: Interferon regulatory factor 1; IRF3: Interferon regulatory factor 3; MAVS: Mitochondrial antiviral signaling protein; MyD88: Myeloid differentiation factor 88; NF-κB: Nuclear factor kappa-B; NKG2D: Natural-killer group 2, member D; NKG2DL: NKG2D ligand; PARP: Poly-ADP-ribose polymerase; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; RIG-I: Retinoic acid-inducible gene I; sEV: Small extracellular vesicles; SSB: Single-strand break; STAT1/3: Signal transducer and activator of transcription 1/3; STING: Stimulator of interferon genes; T1IFN: Type I interferon; TBK1: TANK binding kinase-1; TLR4: Toll-like receptor 4; TNFα: Tumor-necrosis factorα; Tregs: Regulatory T cells; TRIF: TIR-domain-containing adaptor inducing interferon-β)