Anlotinib suppresses homologous recombination via the E2F8-RAD51 axis to activate STING immunity and potentiate PARP inhibitor synthetic lethality in resistant small cell lung cancer

Background Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy that almost invariably acquires resistance to first-line platinum-based chemotherapy, leading to early relapse. PARP inhibitors (PARPi) hold theoretical potential for SCLC due to universal TP53/RB1 deletion, but their monotherapy activity has limited efficacy in unselected relapsed patients. Anlotinib—a multi-target tyrosine kinase inhibitor—has recently been implicated in modulating DNA damage repair, raising the possibility of synergistic interaction with PARPi. However, the molecular basis of such synergy remains entirely unexplored. Methods Cisplatin-resistant SCLC cell models were established and characterized. A potent PARPi was screened, and the synergistic antitumor effects of talazoparib combined with anlotinib were evaluated via in vitro functional assays, multicellular tumor spheroid (MCT), and in vivo xenograft. Mechanisms were explored through transcriptomic, dual-luciferase reporter, rescue experiments, and immunohistochemical validation. Results The combination synergistically suppressed cell viability, anchorage-independent colony formation, and tumor growth versus monotherapies. Mechanistically, it significantly downregulated the E2F8 which was identified as a direct transcriptional activator of RAD51, as luciferase reporter assays showing that E2F8 overexpression increased wild-type RAD51 promoter activity. Rescue experiments demonstrated that E2F8 overexpression restored HR repair and reduced γ-H2AX levels in combination-treated cells. Furthermore, the combination activated the STING-TBK1-IRF3-IFNβ innate immune pathway and, in the MCT, significantly increased CD8 + cytotoxic T cells, CD45 + HLA-DR + activated immune cells and CD4 + helper T cells. Conclusion Anlotinib potentiates the synthetic lethality of talazoparib in drug-resistant SCLC by suppressing E2F8-mediated RAD51 transcription, impairing homologous recombination repair, and inducing persistent DNA damage, while concurrently activating STING-dependent innate immunity. This dual mechanism provides a strong preclinical rationale for combining PARP inhibitors with anlotinib in relapsed SCLC, highlights E2F8/RAD51 as candidate biomarkers warranting further clinical validation, and supports future triplet regimens incorporating immune checkpoint inhibitors.