Figure 3.

Dysfunction of DDR or PARPis induce the cGAS-STING pathway to activate cytosolic immunity. While some DDR dysfunction leads to increased tumor mutation burden (TMB) or tumor neoantigen burden (TNB), which enhances tumor antigenicity, other DDR dysfunction, such as via PARPis, causes stalled replication forks, triggering ATR/CHK1 activation leading to upregulated PD-L1, and replication stress responses inducing fork degradation via several nucleases, including MRE11, EXO1, and MUS81, result in the generation of cytosolic nuclear acids (cNAs). Fork collapse by the above nucleases induces genetic instability and generates micronuclei, which rupture and become cNAs. These cNAs are recognized by pattern recognition receptors (PRRs) as part of the innate immune response, triggering cGAS-STING signaling to increase cytosolic immunity. These acronyms are defined as follows: ALR, AIM2-like receptors; ATR, ataxia-telangiectasia-mutated protein kinase; cGAS, cyclic GMP-AMP synthase; CHK1, checkpoint kinase 1; DDR, DNA damage response; DSB, double strand break; FEN1, flap endonuclease 1; HR, homologous recombination; MMR, mismatch repair deficiency; PD-L1, programmed cell death ligand-1; RLR, RIG1-like receptors; RPA, replication protein A; SSB, single strand break; TLR, Toll-like receptors; NLR, NOD-like receptors; STING, stimulator of interferon genes; XRCC1, X-ray repair cross-complementing 1.