Abstract
Immunotherapy-based combination approaches have improved treatment efficacy in advanced non-small cell lung cancer (NSCLC), but progressive disease remains a challenge. Trilaciclib is a cyclin-dependent kinase 4/6 inhibitor approved for myelopreservation in extensive-stage small cell lung cancer (ES-SCLC). Our results demonstrate that trilaciclib has antitumor potential in NSCLC without significant toxicity. It reprograms the tumor immune microenvironment by primarily increasing antitumor neutrophils and CD8+ T cells. Trilaciclib induces tumor cell senescence and the senescence-associated secretory phenotype in a cGAS-STING-dependent manner, which further facilitates the infiltration and activation of CD177+ neutrophils with anti-tumor properties. These neutrophils enhance CD8+ effector T cell activation and promote antitumor immunity. Additionally, activated CD8+ T cells recruit and activate neutrophils, forming a positive feedback loop. Combining trilaciclib with anti-PD-1 antibodies presents a promising strategy for NSCLC treatment.