(i) ERCC1^WT/WT cells have a functional DDR and adequately maintain genome integrity. (ii) Upon PARPi exposure, exogenous DNA damage is triggered, mostly initiated by PARP1 itself trapped onto the DNA at sites of spontaneous single-strand breaks (SSBs). (iii) During the S phase of the cell cycle, trapped PARP1 generates lesions that prevent the progression of replication forks, leading to fork stalling and subsequent formation of DSBs. In ERCC1^WT/WT cells, most trapped PARP1 lesions are removed, which enables the processing of DSBs through HR and eventually allows replication to restart. Residual inadequately repaired lesions cause moderate formation of CCFs. (iv) The low levels of CCFs generated are unable to trigger the pTBK1/IRF3/NF-κB signaling cascade or subsequent transcription of type I IFN genes; PD-L1 is moderately induced. (v) ERCC1^–/– cells are exposed to increased endogenous DNA damage following the loss of ERCC1. This generates minimal levels of CCFs. (vi) Upon PARPi exposure, ERCC1^–/– cells are subjected to an additional exogenous source of DNA damage. (vii) During the S phase of the cell cycle, trapped PARP1 generates lesions that prevent the progression of replication forks, leading to stalling of forks and subsequent formation of DSBs. In the absence of ERCC1, trapped PARP1 lesions cannot be adequately resolved, which triggers increased DSBs and eventually generates high levels of CCFs. (viii) CCFs are detected by cGAS and, due to the enhanced expression of STING in ERCC1^–/– cells, these efficiently activate cGAS/STING signaling. Activated STING homodimer phosphorylates TBK1, which in turn phosphorylates IRF3 and NF-κB; this triggers their translocation into the nucleus and results in the transcription of type I IFN genes: CCL5 and other type I IFN cytokines are secreted. Higher PD-L1 expression is induced at the cell surface.