Neurodegeneration rewires the tumor microenvironment via the neuro–immune–cancer axis

Abstract

Neurodegeneration and cancer, long considered opposing processes, neuronal loss versus uncontrolled proliferation, are increasingly recognized as mechanistically convergent. This review reframes the field by positioning neurodegeneration as an active driver of tumor evolution. Integrating insights from multi-omics, spatial transcriptomics, and neuroimmune–microbiota studies, we show how degenerating neurons disrupt DNA repair, mitochondrial function, immune regulation, and barrier integrity, thereby creating tumor-permissive niches. Particular emphasis is placed on the enteric nervous system, where neuronal loss promotes colorectal and pancreatic cancers through immune suppression and microbial dysbiosis. Shared molecular regulators, including p53, Pin1, STING, and the Biglycan–IL-10–microbiota axis, exhibit dual roles, pro-apoptotic in neurons yet pro-survival in tumors, highlighting context-dependent biology. We propose a mechanistic, target-based therapeutic classification that transcends disease boundaries. Recognizing neurodegeneration as a tumor-promoting process uncovers novel diagnostic and therapeutic opportunities, expanding cancer neuroscience beyond its current paradigm.