PD-1 blockade exerts antitumor effects by reinvigorating tumor antigen–specific CD8+ T cells. Whereas neoantigens arising from gene alterations in cancer cells comprise critical tumor antigens in antitumor immunity, a subset of non–small cell lung cancers (NSCLCs) harboring substantial tumor mutation burden (TMB) lack CD8+ T cells in the tumor microenvironment (TME), which results in resistance to PD-1 blockade therapy. To overcome this resistance, clarifying the mechanism(s) impairing antitumor immunity in highly mutated NSCLCs is an urgent issue. Here, we showed that activation of the WNT/β-catenin signaling pathway contributed to the development of a noninflamed TME in tumors with high TMB. NSCLCs that lacked immune cell infiltration into the TME despite high TMB preferentially up-regulated the WNT/β-catenin pathway. Immunologic assays revealed that those patients harbored neoantigen-specific CD8+ T cells in the peripheral blood but not in the TME, suggesting impaired T cell infiltration into the TME due to the activation of WNT/β-catenin signaling. In our animal models, the accumulation of gene mutations in cancer cells increased CD8+ T cell infiltration into the TME, thus slowing tumor growth. However, further accumulation of gene mutations blunted antitumor immunity by excluding CD8+ T cells from tumors in a WNT/β-catenin signaling-dependent manner. Combined treatment with PD-1 blockade and WNT/β-catenin signaling inhibitors induced better antitumor immunity than either treatment alone. Thus, we propose a mechanism-oriented combination therapy whereby immune checkpoint inhibitors can be combined with drugs that target cell-intrinsic oncogenic signaling pathways involved in tumor immune escape.