Our findings may be summed up as follows: (a) MTH1 inhibition confers an M1 phenotype among TAMs (through, at least in part, extracellular DNA/TLR9/NFkB signaling); (b) MTH1 inhibition stimulates CD8 T cell activation and tumor infiltration; and (c) treatment with an MTH1 inhibitor improves the efficacy of anti-PD-L1 treatment in experimental mesothelioma by favoring macrophage M1 polarization and DC activation and enhancing T cell tumor infiltration and activation triggered by immunotherapy. Here, TLR9 is linked to neoplasm.