Retinoic acid receptor responder protein 2 (RARRES2) is a small secreted protein involved in multiple cancers, including adrenocortical carcinoma (ACC). Serum RARRES2 may be used as a novel prognostic marker for ACC. Retinoic acid receptor responder 2 (RARRES2) is transcriptionally downregulated in multiple cancer types. Previous studies suggested that it can serve as an immune-dependent tumor suppressor by acting as a chemoattractant to recruit anticancer immune cells expressing its receptor, the chemerin chemokine receptor 1 (CMKLR1), to sites of tumor. Mechanistically, RARRES2 overexpression in ACC cells inhibited Wnt/beta-catenin pathway activity by promoting beta-catenin phosphorylation and degradation, it also inhibited the phosphorylation of p38 mitogen-activated protein kinase. Thus RARRES2 is a novel tumor suppressor for ACC, which can function through an immune-independent mechanism.