e14552 Background: PARP1 promotes tumor survival through compensatory DNA-repair pathways and inflammatory signaling. While PARP inhibitors (PARPi) are most effective in BRCA-deficient tumors, their immunoregulatory roles remain poorly defined. Given the rarity of BRCA mutations and limited clinical outcome of PARPi in colorectal cancer (CRC), defining BRCA-independent immune regulatory role of PARP1 is critical. Understanding how PARPi modulates antitumor immunity and the key drivers of immune evasion may broaden the therapeutic utility of PARPi beyond DNA-repair-deficient tumors. Methods: We evaluated the PARPi, olaparib and talazoparib across three murine CRC models. Mice received escalating doses of PARPi, immune checkpoint blockade (anti-CTLA-4 or anti-PD-1), or combined PARPi and checkpoint blockade. Clinical scoring and tumor burden were assessed longitudinally. Tumor-infiltrating immune cells were phenotypically and functionally characterized, and cytokine production was quantified. Myeloid-derived suppressor cells (MDSCs) were isolated from tumor-bearing mice or generated ex vivo from human-derived bone marrow cells, then treated and evaluated after treatment in a co-culture system using a T-cell suppression assay. Results: PARP1 inhibition with low-to-moderate doses of olaparib significantly reduced tumor burden across CRC models, whereas higher doses were ineffective or even promoted tumor growth. Both olaparib and talazoparib impaired the activity of tumor-infiltrating MDSCs and T-reg cells by downregulating key immunosuppressive mediators, including Arg1, iNOS, and COX-2. Treated tumors exhibited increased CD8⁺ T-cell infiltration, and adoptive transfer of untreated MDSCs reversed the antitumor effects of PARP inhibition. Similarly, treatment with PARPi abrogated the suppressive activity of human-derived MDSCs in CFSE-based T-cell co-culture assays. Both inhibitors synergized with anti-PD-1 and anti-CTLA-4 therapy, resulting in complete tumor regression. Conclusions: PARP inhibition exerts dose-dependent immunoregulatory effects that reshape the CRC microenvironment by suppressing MDSC and T-reg functions while restoring antitumor T-cell responses. These findings reveal a previously underappreciated immune function of PARP1 and demonstrate that partial, rather than maximal, inhibition is optimal for antitumor immunity. The results support refining PARPi dosing strategies and clinical evaluation of PARP1-targeted therapies to enhance responsiveness to checkpoint blockade in CRC, with potential applicability across other gastrointestinal cancers. Overall, these data identify PARP1 as an immunoregulator and provide a compelling therapeutic rationale for clinical evaluation of PARPi in combination with PD-1 and CTLA-4 inhibitors to overcome immunotherapy resistance in CRC.
Abouzeid et al. (Thu,) studied this question.