Immunotherapy has revolutionized the treatment of oncologic patients. However, the target and extent of the immunomodulatory effect of different immune checkpoint inhibitors (ICIs) have not been fully elucidated. Taking advantage of a murine model of spontaneous thyroid cancer and single cell multi-omic analysis, we investigated the effect of three different ICIs on tumor progression and CD45+ organ infiltrating cells. We uncovered a broad, specific, tunable effect of ICIs. Our findings provide unexpected insights into the immunobiology of ICIs and highlight potential strategies for the optimization of immunotherapies.