Targeting FOXM1 reshapes antitumor immunity to attenuate small cell lung cancer progression

Small cell lung cancer (SCLC) is a lethal lung malignancy, which is associated with distant metastasis and chemoresistance. Due to the limited availability of targeted therapies, identifying a potential therapeutic target is a pressing unmet need in SCLC. Single-cell and bulk-transcriptomic datasets were analyzed that revealed FOXM1 as a potential targeting candidate in SCLC. High FOXM1 expression was observed in human and murine SCLC tissues and cell lines. Interestingly, chemoresistant (CR) SCLC cells exhibited substantially higher FOXM1 expression compared to naïve SCLC. Furthermore, FOXM1 inhibition in combination with platinum-based chemotherapy showed synergistic anticancer effects in vitro and in vivo xenograft and spontaneous (RPM: RB1^fl/fl; TP53 ^fl/fl; LSL-MYCT58A) mouse models of SCLC. Mechanistically, RNA-seq analysis revealed that FOXM1 inhibition altered the Aurora Kinase B (AURKB) signaling pathway. Notably, FOXM1 inhibition enhanced T cell activation, supported differentiation of CD8⁺ T cells, and T cell-mediated killing of SCLC cells. Additionally, FOXM1 inhibition enhanced CD8⁺ T cell and macrophage recruitment in the tumor microenvironment (TME) of immunocompetent RPM model. This study demonstrates that FOXM1 targeting small molecule inhibitors (FOXM1i) has the potential to be a novel therapeutic strategy to combat SCLC progression, including chemotherapeutic resistance and reshaping the anti-tumor immune response.