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. In this study, 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 gastric cancer 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. Although this immunosuppressive macrophage infiltration was associated with resistance to PD-1 blockade monotherapy, it predicted a response to combination treatment: 8 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 platelet-derived growth factor receptor α (PDGFRα)/fibroblast growth factor receptor (FGFR)-dependent p38 mitogen-activated protein kinase (MAPK) and AKT signaling pathways in F4/80highCD11bint immunosuppressive macrophages, triggering endoplasmic reticulum stress and an unresolved unfolded protein response, resulting 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 gastric cancer, enabling mechanism-based combination cancer immunotherapy.