XPO1-mediated TRIM21 nuclear export reprograms TREM2+ macrophage polarization by targeting IRF3 to augment anti-PD-1 efficacy in small cell lung cancer
Small cell lung cancer (SCLC) is an aggressive malignancy that responds poorly to immune checkpoint inhibitor (ICI) therapy, due to its immunosuppressive tumor microenvironment. Here, we analyse preclinical mouse tumor models and patient-derived SCLC samples and identify Exportin 1 (XPO1) as a regulator of immune suppression in SCLC. Mechanistically, XPO1 drives the nuclear export of TRIM21, enabling TRIM21-dependent proteasomal degradation of IRF3 and repressing the immunostimulatory cytokine TNFSF15. Loss of TNFSF15 promotes TREM2+ macrophage polarization, which subsequently attenuates macrophage-dependent IFN-γ-STAT1 signaling and MHC class I expression in tumor cells. Pharmacological or genetic XPO1 blockade restores TNFSF15, constrains TREM2+ macrophage differentiation, reactivates antigen presentation, and enhances anti-PD-1 efficacy in preclinical mouse models. Thus, our findings link XPO1-dependent nuclear export to TREM2+ macrophage polarization and support evaluation of XPO1 inhibition in combination with ICIs in SCLC. Small cell lung cancer (SCLC) is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment (TME) resistant to Immune checkpoint inhibitor (ICI) therapy. Here, the authors define an XPO1-TRIM21-TNFSF15 axis that promotes the polarization of immunosuppressive TREM2+ macrophages, which ultimately orchestrates immune exclusion by impairing antigen presentation. Importantly, targeting XPO1 enhances the efficacy of anti-PD1 immunotherapy in mice.