Abstract 414P
Background
Cisplatin, a cornerstone of chemotherapy for non-small cell lung cancer (NSCLC), not only exerts direct cytotoxic effects but also modulates the tumor immune microenvironment (TIME). However, the mechanisms through which cisplatin reshapes the TIME via exosomal pathways and contributes to immune evasion remain unclear.
Methods
This study investigated the role of Sphingosine kinase 1 (SPHK1) in NSCLC using in vivo and in vitro models. In vitro experiments explored the effect of cisplatin on the SPHK1/S1P pathway via E2F1 and investigated the specific mechanism of exosomal sorting of SPHK1 mRNA. In vivo experiments assessed the effect of SPHK1 on tumor progression and immune microenvironment via exosomes through a mouse lung cancer model. In addition, the prospect of targeting SPHK1 for the treatment of NSCLC patients was explored.
Results
Our results demonstrate that cisplatin upregulates SPHK1 expression via E2F1-mediated transcription and promotes the loading of SPHK1 mRNA into exosomes through the RNA-binding protein STAU1. Exosome-mediated transfer of SPHK1 mRNA enhances tumor proliferation, immune evasion, and PD-L1 expression while suppressing cytotoxic T-cell infiltration and activation. Therapeutically, SPHK1 inhibition using the small-molecule inhibitor PF543 or a novel siRNA-based nanomedicine (AuSi) improved suppressive TIME and enhanced anti-PD-1 antibody efficacy in preclinical models. The combination of SPHK1-targeted therapies with cisplatin and anti-PD-1 significantly reduced tumor growth and lung metastases, while reinvigorating antitumor immunity. Mechanistically, SPHK1-driven exosomal pathways represent a broader framework for understanding treatment responsiveness in malignancies.
Conclusions
This study provides a comprehensive mechanism by which cisplatin remodels the TIME in NSCLC and highlights the translational potential of SPHK1-targeted therapies.
Funding
The National Natural Science Foundation of China
Disclosure
All authors have declared no conflicts of interest.