PARP inhibitor combined with platinum activates the cGAS-STING pathway to enhance anti-PD-L1 immunotherapy in lung adenocarcinoma

Purpose: Despite significant advances in immunotherapy, lung adenocarcinoma (LUAD) remains challenging to treat due to its low immunogenicity. Platinum-based chemotherapy is a well-established DNA-damaging agent. PARP Inhibitor is effective for tumors with DNA repair defects while showing limited efficacy in BRCA-proficient non-small cell lung Cancer (NSCLC). This study investigated whether combining a PARP Inhibitor with platinum chemotherapy enhances the response to PD-L1 blockade in LUAD and elucidated the underlying mechanism.

Method: Immunoblotting, colony formation assays, Real-Time PCR, immunofluorescence, flow cytometry, and immunohistochemistry were employed to investigate the underlying mechanisms in cell lines and the tumor microenvironment. The LLC tumor model was used to assess the efficacy of the combination of PARP inhibitors, platinum, and PD-L1 blockade. Clinical relevance was explored using public databases.

Results: PARP Inhibitor synergized with platinum to activate the cGAS-STING pathway, leading to an upregulation of PD-L1 expression and stimulation of type I interferon responses in LUAD cells. In LLC mouse models, the triple combination most effectively suppressed tumors, increased dendritic cell and CD8⁺ T-cell infiltration, thereby augmenting anti-tumor immunity. Clinical data linked high PARP1 expression to MDSC infiltration and poor prognosis, and emerging trial evidence supports this combinatorial strategy.

Conclusion: The combination of PARP inhibitors and platinum activates the cGAS-STING pathway, leading to increased infiltration of mature DCs and CD8⁺ T cells, thereby sensitizing NSCLC to anti-PD-L1 therapy. This study presents a promising strategy for treating patients with LUAD with low immunogenicity and poor prognosis.

CD8(+)T cell; LUAD; PARP inhibitor; PD-L1; Platinum; cGAS-STING.