SignificanceTregs are essential in restraining immune responses for immune homeostasis. SRC-3 (Steroid receptor coactivator 3) is a pleiotropic coactivator, the second most highly expressed transcriptional coactivator in Tregs, and a suspect in Treg function. The disruption of SRC-3 expression in Tregs leads to a “complete lifetime eradication” of tumors in aggressive syngeneic breast cancer mouse models because deletion of SRC-3 alters the expression of a wide range of key genes involved in efferent and afferent Treg signaling. SRC-3KO Tregs confer this long-lasting protection against cancer recurrence in mice without an apparent systemic autoimmune pathological phenotype. Therefore, treatment with SRC-3-deleted Tregs could represent an efficient future target for eliminating tumor growth and recurrence without the autoimmune side effects that typically accompany immune checkpoint modulators.