Olaparib Combined with Anti-PD1 Enhances Immunotherapy of Gastric Cancer Via NF-κB/c-Myc/PD-L1 Signaling.

BACKGROUND: PARP inhibitors, effective in BRCA-mutated cancers, show potential in gastric cancer (GC) where homologous recombination defects (e.g., BRCA1/2 mutations) are common. Olaparib, a PARP inhibitor, upregulates PD-L1, suggesting synergy with PD-1 inhibitors for enhanced GC therapy. METHODS: Using CCK-8 screening of 867 drugs, olaparib demonstrated potent GC cell inhibition. Western blot and qRT-PCR assessed PD-L1, c-MYC, COX-2, and NF-κB pathway proteins (p65/p-p65). Functional assays (Transwell, wound healing, colony formation) evaluated olaparib's effects on GC cell proliferation, migration, and invasion. A GC mouse model tested olaparib combined with anti-PD1. TCGA and Kaplan-Meier analyzed PARP expression-prognosis correlations. RESULTS: Olaparib suppressed GC cell proliferation, migration, and invasion in vitro. Western blot revealed upregulated c-MYC, COX-2, p65, p-p65, and PD-L1, confirmed by qRT-PCR for PD-L1. Low PARP expression correlated with better GC patient survival. In vivo, olaparib synergized with anti-PD1 to enhance tumor suppression. CONCLUSION: Olaparib activates the NF-κB/c-MYC pathway to elevate PD-L1, supporting its combination with PD-1 inhibitors as a promising GC therapeutic strategy.