<p>The serotonin axis, encompassing the biosynthesis, transport, receptor signaling and metabolism of serotonin, has emerged as a context-dependent regulatory network implicated in cancer biology. Beyond its classical neurotransmitter functions, serotonin modulates tumor progression through receptor-dependent signaling pathways and non-canonical mechanisms such as histone serotonylation, which directly links cellular metabolism to epigenetic regulation. Available evidence suggests that these processes can influence tumor cell proliferation, metabolic adaptation, plasticity and therapeutic drug resistance. Furthermore, the serotonin axis plays a context-dependent role in shaping the tumor microenvironment by regulating the functions of T cells, macrophages and other stromal components, thereby influencing responses to cancer immunotherapy. These diverse regulatory mechanisms have prompted the development of therapeutic strategies targeting serotonin biosynthesis and metabolism, serotonin transport, receptor signaling, and serotonylation, although their efficacy remains highly context-dependent. We further discuss emerging mechanistic insights, unresolved questions, and the opportunities and challenges for developing context-dependent therapeutic strategies targeting this axis.</p>