The molecular mechanisms responsible for the high immunosuppressive capacity of CD4⁺ Tregs in tumors are not well known. High-dimensional single-cell profiling of T cells from chemotherapy-naive individuals with non–small-cell lung cancer identified the transcription factor IRF4 as specifically expressed by a subset of intratumoral CD4⁺ effector Tregs with superior suppressive activity. In contrast to the IRF4^– counterparts, IRF4⁺ Tregs expressed a vast array of suppressive molecules, and their presence correlated with multiple exhausted subpopulations of T cells. Integration of transcriptomic and epigenomic data revealed that IRF4, either alone or in combination with its partner BATF, directly controlled a molecular program responsible for immunosuppression in tumors. Accordingly, deletion of Irf4 exclusively in Tregs resulted in delayed tumor growth in mice while the abundance of IRF4⁺ Tregs correlated with poor prognosis in patients with multiple human cancers. Thus, a common mechanism underlies immunosuppression in the tumor microenvironment irrespective of the tumor type.