Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) plays a dual role in cancer initiation and progression. Identifying signals that modulate the function of SHP2 can improve current therapeutic approaches for IFN-α/β in HCC. We showed that cAMP-dependent protein kinase A (PKA) suppresses IFN-α/β-induced JAK/STAT signaling by increasing the phosphatase activity of SHP2, promoting the dissociation of SHP2 from the receptor for activated C-kinase 1 (RACK1) and binding to STAT1. Additionally, cAMP-degrading phosphodiesterase 4D5 (PDE4D) physically interacts with RACK1 to regulate PKA-mediated SHP2 activity and STAT1 phosphorylation. IFN-α activates PKA by inducing the expression of cyclooxygenase 2 (COX2) and the production of prostaglandin E2 (PGE2), which in turn stimulates the binding of SHP2 to IFNAR2 via RACK1. A COX inhibitor aspirin potently increases the antitumor effects of IFN-α in the suppression of HCC cell proliferation in vivo. Higher expression of COX2 and phosphorylated STAT3 is associated with poor development and prognosis in HCC patients by analyzing human HCC clinical samples. These observations suggest that a fundamental PKA/SHP2-dependent negative feedback loop acts on IFN signaling, and inhibition of this signaling by the selective COX2 inhibitors may enhance the clinical efficacy of type I IFNs in treating HCC.Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.