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2 Immunotherapies targeting Programmed death 1 (PD-1) co-inhibitory receptor have shown great promise for a subset of cancer patients. However, robust and safe combination therapies are still needed to bring the benefit of cancer immunotherapy to broader patient populations. To search for an optimal strategy of combinatorial immunotherapy, we have compared the antitumor activity of anti-4-1BB/anti-PD-1 combination with that of anti-PD-1/anti-LAG-3 combination in the poorly immunogenic B16F10 melanoma model. Pronounced tumor inhibition occurred only in animals receiving anti–PD-1 and anti–4-1BB concomitantly, while combining anti-PD-1 with anti-LAG-3 led to a modest degree of tumor suppression. The activity of anti-4-1BB/anti-PD-1 combination was dependent on IFN and CD8+ T cells. Both 4-1BB and PD-1 proteins were elevated on the surface of CD8+ T cells by anti-4-1BB/anti-PD-1 co-treatment. In the tumor microenvironment, an effective antitumor immune response was induced as indicated by increased CD8+/Treg ratio and the enrichment of genes such as CD3, CD8, IFN an