Significance The evolution of peripheral immune cell abundance and signaling over time, as well as how these immune cells interact with the tumor, may impact a cancer patient’s response to therapy. By developing an ecological population model, we provide evidence of a dynamic predator–prey-like relationship between circulating immune cell abundance and tumor size in patients that respond to immunotherapy. This relationship is not found either in patients that are nonresponsive to immunotherapy or during chemotherapy. Single-cell RNA sequencing of serial peripheral blood samples from patients shows that the strength of tumor–immune cell interactions is reflected in T cells’ interferon activation and differentiation early in treatment. Thus, circulating immune cell dynamics reflect a tumor’s response to immunotherapy.