Lenvatinib combined with PD-1 blockade therapy benefits gastric cancers through immunosuppressive macrophage modulation.

The combination of multikinase inhibitors with PD-1 blockade therapy has emerged as a promising strategy to overcome resistance to PD-1 blockade monotherapy across multiple cancer types, including gastric cancer (GC). Here, we report that the multikinase inhibitor lenvatinib selectively reduced the number of CD206+CD163+ immunosuppressive macrophages in the tumor microenvironment (TME) and increased antitumor immunity. Longitudinal immunoprofiling was conducted with paired (pre- and posttreatment) tumor samples from patients with advanced GC who received first- or second-line combination therapy with lenvatinib and pembrolizumab in the EPOC1706 clinical trial. Patients with abundant CD206+CD163+ immunosuppressive macrophage infiltration exhibited favorable responses to combination therapy, accompanied by a significant posttreatment reduction in these cells. While this immunosuppressive macrophage infiltration was associated with resistance to PD-1 blockade monotherapy, it predicted a response to combination treatment: eight of the 9 patients with >440 CD206+CD163+ immunosuppressive macrophages/mm² responded, whereas none of the 8 patients who received monotherapy responded. Mechanistically, lenvatinib inhibited PDGFRα (platelet-derived growth factor receptor α)/FGFR (fibroblast growth factor receptor)-dependent p38 MAPK (mitogen-activated protein kinase) and AKT signaling pathways in F4/80highCD11bint immunosuppressive macrophages, triggering endoplasmic reticulum stress and an unresolved unfolded protein response, resulting 4 in their apoptosis. Furthermore, in multiple animal models, the therapeutic efficacy of the combination was observed in tumors with abundant immunosuppressive macrophages with activated PDGFR/FGFR-AKT/p38 MAPK signaling. Therefore, we propose that the abundance of immunosuppressive macrophages in the TME could serve as a predictive biomarker for patient stratification to guide rational anti-PD-1-based combination therapy in GC, enabling mechanism-based combination cancer immunotherapy.