Cancer Neuroscience: From Hallmark‐Enabling Biology to a Therapeutic Pillar

The next advance in cancer therapy may depend not only on what malignant cells become, but also on how they engage the systems that regulate the host.Cancer neuroscience has established that neural signaling can influence tumor initiation, progression, immune escape, and treatment resistance, including in cancers arising outside the central nervous system [ 1,2 ].The opportunity is therefore larger than adding nerves to descriptions of the tumor microenvironment.It is to build a therapeutic discipline with three connected responsibilities: disrupting neural mechanisms that sustain malignancy, preserving and restoring nervous-system function, and treating the symptoms and psychological suffering that shape patients' lives.These responsibilities should be judged together, without requiring every intervention to improve every outcome.The evolution of the cancer hallmarks provides a framework for this transition.The original formulation organized malignancy around six acquired capabilities; subsequent iterations incorporated immune evasion, altered metabolism, plasticity, and an increasingly explicit account of the microenvironment [3][4][5].In 2023, Hanahan and Monje positioned neuronal interactions as mechanisms that facilitate multiple hallmark capabilities, and the 2026 framework explicitly incorporated innervation among the hallmark-enabling phenotypic characteristics, distinct from the nine acquired functional capabilities [ 6,7 ].This distinction matters.Cancer neuroscience is a field, not itself a cellular capability; its biological claim is that malignant tissues can recruit, remodel, and exploit neural regulation to acquire several capabilities required for cancer.Calling this biology hallmark-enabling should strengthen rather than diminish its therapeutic significance.A process that coor-dinates proliferation, immunity, metabolism, and dissemination may offer opportunities precisely because it crosses conventional mechanistic boundaries.Yet incorporation into the hallmark framework is not a declaration that every tumor requires innervation, that every nerve promotes cancer, or that neural targeting is clinically validated across malignancies [ 7 ].The useful question is not whether a tumor contains nerves, but which neural interactions are necessary for its behavior and whether those interactions can be altered safely.