Patients with cancer with liver metastasis demonstrate significantly worse outcomes than those without liver metastasis when treated with anti–PD-1 immunotherapy. The mechanism of liver metastases–induced reduction in systemic antitumor immunity is unclear. Using a dual-tumor immunocompetent mouse model, we found that the immune response to tumor antigen presence within the liver led to the systemic suppression of antitumor immunity. The immune suppression was antigen specific and associated with the coordinated activation of regulatory T cells (T_regs) and modulation of intratumoral CD11b⁺ monocytes. The dysfunctional immune state could not be reversed by anti–PD-1 monotherapy unless T_reg cells were depleted (anti–CTLA-4) or destabilized (EZH2 inhibitor). Thus, this study provides a mechanistic understanding and rationale for adding T_reg and CD11b⁺ monocyte targeting agents in combination with anti–PD-1 to treat patients with cancer with liver metastasis.