Cyclic adenosine monophosphate signaling pathway in tumor-associated macrophages: molecular mechanisms and tumor...

Tumor-associated macrophages (TAMs) are the core innate immune cells in the tumor microenvironment (TME), and their phenotypic polarization and functional reprogramming determine the orientation of the tumor immune microenvironment and the efficacy of immunotherapy. As a key intracellular second messenger, cyclic adenosine monophosphate (cAMP) acts as a central hub regulating TAM function by activating two major downstream effector pathways: protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). This article systematically reviews the molecular mechanisms by which the cAMP-PKA/Epac signaling pathway regulates TAMs, the upstream regulatory factors in the TME, and targeted tumor immunotherapy strategies for this pathway. Studies have shown that cAMP mainly induces TAMs to polarize toward a protumor "M2-like phenotype" through two classical pathways: cAMP-PKA-cyclic AMP response element-binding protein (CREB) and cAMP-PKA-signal transducer and activator of transcription 3/6 (STAT3/6). Meanwhile, it enhances the immunosuppressive, proangiogenic, and profibrotic functions of TAMs via the cAMP-Epac pathway, inhibition of nuclear factor kappa-B (NF-κB) signaling, and attenuation of M1 polarization. Furthermore, lactate and hypoxia-inducible factor-1α (HIF-1α) in the TME can further activate the intracellular cAMP signaling pathway in TAMs by activating G protein-coupled receptors (GPCRs) and regulating the expression of adenylate cyclase, forming a cascade regulatory network with cAMP that exacerbates tumor immunosuppression. In addition, targeting the cAMP metabolic process, the downstream PKA pathway, and key molecules such as CREB/STAT/NF-κB can effectively reverse the "M2-like phenotype" of TAMs and restore their antitumor functions. Combination with immune checkpoint inhibitors can also significantly enhance the efficacy of tumor immunotherapy. By summarizing the core mechanisms of the cAMP-TAM regulatory axis and targeted intervention strategies, this article provides theoretical references and potential target directions for the development of novel tumor immunotherapy regimens based on TAM reprogramming.