The Brain-tumor axis: Tumor pathogenesis and therapeutic strategies from a cancer neuroscience perspective.

Cancer research has undergone a fundamental paradigm shift, moving beyond a tumor-cell-centric framework toward a systems-level understanding in which the nervous system occupies a central regulatory role. The brain and its peripheral extensions engage in sophisticated, bidirectional crosstalk with tumors across multiple biological scales. This complex relationship, now termed the brain-tumor axis, operates through mechanisms spanning systemic neuroendocrine regulation, local neural-tumor interactions, and the distinctive biology of the central nervous system as both a primary and metastatic tumor site. At the systemic level, the brain modulates distant tumors via stress-responsive neuroendocrine pathways and discrete central-peripheral neural circuits that govern catecholaminergic innervation and antitumor immune surveillance. Neuropeptide systems further serve as integrative messengers within this axis, acting via G protein-coupled receptors on malignant, stromal and immune cells to orchestrate proliferation, stromal remodeling and immune polarization. Within the tumor microenvironment, neural-tumor interactions encompass perineural invasion, Schwann-cell-mediated pro-tumorigenic reprogramming, and neural remodeling of the immune landscape. In primary brain tumors, malignant cells integrate into host neural circuits and exploit glial plasticity to sustain proliferation and immune evasion. For metastatic disease, circulating tumor cells breach the blood-brain barrier and adapt to the brain parenchyma through dynamic interactions with resident astrocytes and microglia. We further discuss the remote consequences of tumors on nervous-system homeostasis, including cancer-induced pain, cognitive impairment, and cachexia, and survey emerging therapeutic strategies targeting this axis, from β-adrenergic blockade and neurotrophic signaling inhibition to physical neuromodulation. We propose that the brain-tumor axis represents an emerging integrative hallmark of cancer, defined by the context-dependent duality of neural signaling, whereby identical pathways elicit opposing pro- or anti-tumorigenic effects contingent on tumor type, disease stage, and microenvironmental context. Collectively, these insights position cancer neuroscience as a transformative frontier in precision oncology and signal a conceptual transition toward brain-tumor-axis-based treatment paradigms.