DISCUSSION DDR inhibition and ICB are both therapeutic strategies under preclinical and clinical development for patients with SCLC.Here, we report a previously unexplored role of DDR pathway targeting in regulating antitumor immune response in SCLC models, specifically that inhibition of DDR proteins such as CHK and PARP potentiates the antitumor immune response of PDL blockade through T cellmediated effects.This effect is mediated through activation of the STING TBKIRF innate immune response pathway, which ultimately enhances expression of the type interferon gene IFN and downstream chemokines such as CXCL and CCL to induce activation and function of cytotoxic T lymphocytes.Despite having one of the highest mutational burdens among solid tumors, SCLC paradoxically shows lower expression of PDL and relatively immunosuppressed phenotypes with low levels of infi ltrating T cells and reduced antigen presentation. Recent clinical data illustrating that tumors with defective DDR, such as microsatellite instabilityhigh or mismatch repairdeficient tumors, predict improved response to anti PD therapy support the hypothesis that the addition of a DDR inhibitor to antiPD therapy may significantly enhance response rates and outcomes. However, it is not known to what extent pharmacologic inhibitors of DDR targets may enhance ICB response or the mechanism through which this occurs.SCLC exhibits ubiquitous loss in two key regulators of the DNA damage and cellcycle checkpoint pathway, TP and RB, which leads to high genomic instability and replication stress. Therefore, we hypothesized that targeting this inherent DNA repair vulnerability with DDR inhibitors to promote an immune response may be an reasch Fipronil effective strategy to achieve a quick and sustained antitumor immune response by potentiating the effect of a combination ICB regimen.Previous studies have reported the presence of cytosolic DNA postS phase damage, and additional evidence suggests that cells may actively export DNA fragments from the nucleus, possibly to prevent misincorporation into genomic DNA. Here, we demonstrated increased cytosolic DNA following treatment with either DDR inhibitor in vitro.IRF knockdown studies confirmed the role of the transcription factor in the DDR targetingmediated antitumor immune response and PDL regulation in SCLC.In the proposed model, targeting the DDR proteins PARP and CHK with the smallmolecule inhibitors prexasertib and olaparib leads to cytosolic DNA in SCLC models.The cytosolic DNA is then recognized by cGAS, which leads to activation of the STING TBKIRF pathway.IRF activation leads to increased expression of IFN and enhanced expression of the chemokines CXCL and CCL.Finally, DDR cotargeting leads to enhanced antitumor immunity in SCLC models.Moreover, in our models we demonstrated significant increase in the expression of the chemokines CXCL and CCL after DDR inhibitor treatment.It is not known to what extent increased tumor mutation burden induced by DDR targeting may also contribute to enhancing ICB response.However, based on our observations here with tumor shrinkage starting soon after treatment, the rapid innate responserather than changes in neoantigensseems likely to be a more important contributor at least in the initial response.The pathway also leads to the upregulation of PDL expression.Expression of PDL is associated with tumors deficient in DNA damage repair, and we, for the first time, provide rationale for investigating the role of immunotherapy in the context of DDR targeting in SCLC.