Cancer is a complex disease influenced by genetic and environmental factors, with the tumor microenvironment (TME) playing a critical role in its progression. Cyclic adenosine monophosphate (cAMP) is a second messenger that has pleiotropic effects on the TME, influencing both cancer cells and stromal cells. cAMP can activate protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), promoting or inhibiting cancer cell growth and survival, depending on the context and cancer type. Tumor-associated stromal cells, such as cancer-associated fibroblasts (CAFs) and immune cells, release cytokines and growth factors that modulate cAMP production in the TME. Recent studies have shown that targeting cAMP signaling in the TME has therapeutic benefits, with small-molecule agents inhibiting adenylate cyclase and PKA, and cAMP-elevating agents like forskolin inducing cancer cell death and inhibiting proliferation. This review summarizes the current understanding of cAMP signaling in cancer biology and immunology, highlighting its context-dependent dual role in oncogenesis. Understanding the precise mechanisms by which cAMP and the TME interact in cancer is crucial for developing effective therapies. Future research on the cAMP-cancer axis and its regulation in the TME may provide new insights into tumorigenesis and lead to novel therapeutic strategies.Cancer is a complex disease influenced by genetic and environmental factors, with the tumor microenvironment (TME) playing a critical role in its progression. Cyclic adenosine monophosphate (cAMP) is a second messenger that has pleiotropic effects on the TME, influencing both cancer cells and stromal cells. cAMP can activate protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), promoting or inhibiting cancer cell growth and survival, depending on the context and cancer type. Tumor-associated stromal cells, such as cancer-associated fibroblasts (CAFs) and immune cells, release cytokines and growth factors that modulate cAMP production in the TME. Recent studies have shown that targeting cAMP signaling in the TME has therapeutic benefits, with small-molecule agents inhibiting adenylate cyclase and PKA, and cAMP-elevating agents like forskolin inducing cancer cell death and inhibiting proliferation. This review summarizes the current understanding of cAMP signaling in cancer biology and immunology, highlighting its context-dependent dual role in oncogenesis. Understanding the precise mechanisms by which cAMP and the TME interact in cancer is crucial for developing effective therapies. Future research on the cAMP-cancer axis and its regulation in the TME may provide new insights into tumorigenesis and lead to novel therapeutic strategies.