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.