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Diverse combination therapies are being investigated to overcome the limitations of immune checkpoint inhibitors. However, determining the optimal combination therapy remains a challenge. Herein, we demonstrated improved anti-tumor effects through combination treatment with denfivontinib and pembrolizumab. The combination treatment resulted in enhanced differentiation into effector CD4⁺ and CD8⁺ T cells, accompanied by an increase in IFN-γ expression in the YHIM-2004 NSCLC patient-derived xenograft model. Concurrently, a reduction in immunosuppressive M2 macrophages and myeloid-derived suppressor cells was observed. Mechanistically, denfivontinib potentiates the NOD-like receptor pathway, thereby facilitating the formation of the NLRP3 inflammasome. This leads to macrophage activation through an increase in the NF-kB signaling pathways. The NLRP3 inflammasome score influenced enhanced immune response in NSCLC patient data undergoing anti-PD-1 immunotherapy, suggesting role of NLRP3 inflammasome in activating immune response during treatment. This study provides insights into immune-mediated anti-cancer effects of denfivontinib in combination with pembrolizumab.