Blocking the nuclear export protein Exportin 1 improves the response to anti-PD-1 immune checkpoint therapy in small cell lung cancer, according to research published in Nature Communications. Scientists identified Exportin 1, or XPO1, as a critical driver of immune evasion after studying patient-derived small cell lung cancer samples and preclinical mouse models.
Small cell lung cancer remains an aggressive malignancy that typically responds poorly to immune checkpoint inhibitors due to an immunosuppressive tumor microenvironment. In the study, researchers determined that XPO1 drives the nuclear export of TRIM21. This process enables TRIM21 to trigger the proteasomal degradation of IRF3, which directly represses the immunostimulatory cytokine TNFSF15.
The loss of TNFSF15 drives the polarization of TREM2-positive macrophages. These polarized macrophages subsequently weaken macrophage-dependent IFN-γ-STAT1 signaling and reduce MHC class I expression on tumor cells, preventing the immune system from properly recognizing the cancer.
Genetic and pharmacological blockade of XPO1 halted this suppressive cascade in preclinical models. Inhibiting XPO1 restored TNFSF15 production, restricted TREM2-positive macrophage differentiation, reactivated tumor antigen presentation, and enhanced the efficacy of anti-PD-1 checkpoint inhibitor treatment.
Researchers from Tianjin Medical University Cancer Institute and Hospital, the Affiliated Cancer Hospital of Zhengzhou University, and Nankai University collaborated on the project. Qingwu Du, Tingting Qin, and Jingya Wang contributed equally as co-lead authors. The project received funding from the National Natural Science Foundation of China grant 82272686, the Natural Science Foundation of Tianjin grant 25JCYBJC00270, the Tianjin Key Medical Discipline Construction Project grant TJYXZDXK-3-003A, and the Clinical-Basic Co-PI Program grant 20250103. Professor Kate D. Sutherland from the University of Melbourne provided RP116 cells for the research.
