Lurbinectedin sensitizes PD-L1 blockade therapy by activating STING-IFN signaling in small-cell lung cancer.

Lurbinectedin is an approved second-line treatment for small-cell lung cancer (SCLC). SCLC clinical trials combining lurbinectedin with PD-L1 blockade are currently ongoing. However, the immunomodulatory effects of lurbinectedin remain largely unknown. In this study, we demonstrate that lurbinectedin treatment activates the STING pathway, which increases interferon (IFN) signaling, pro-inflammatory chemokines, and major histocompatibility complex class I (MHC-I) in SCLC models. Lurbinectedin treatment augments the anti-tumor immune response of PD-L1 blockade with significant tumor regression in first-line and maintenance settings in SCLC mouse models. In vivo, lurbinectedin treatment increases CD8⁺ T cells and M1 macrophages and decreases immunosuppressive M2 macrophages. STING and CD8 depletion reverses the anti-tumor response. Interestingly, our study shows that lurbinectedin treatment upregulates MHC-I/II genes and CD8 in SCLC clinical samples. We provide mechanistic insights into the effect of lurbinectedin on STING-mediated multimodal immune activation and demonstrate that lurbinectedin treatment represents a promising therapeutic strategy to potentiate the efficacy of immunotherapy in SCLC.