Tumor neuromicrobiology: Toward an integrative framework of neural–microbial–immune crosstalk in cancer

The nervous system and the gut microbiota have emerged as critical regulators of tumor biology, and accumulating evidence indicates that their roles in cancer are interconnected. In this review, we synthesize recent advances to outline an integrative perspective—which we refer to as tumor neuromicrobiology—that conceptualizes a hierarchical, multiscale network linking neural signaling, microbial ecology, and immune regulation. We describe three spatially and functionally interrelated tiers: (i) a macro-scale systemic axis connecting stress-responsive neural pathways, gut microbiota, and systemic immunity; (ii) a meso-scale organ axis, exemplified by the gut as a prototypical neuromicrobial interface; and (iii) a conditional micro-scale tumor microenvironment axis in which high-proximity interactions among nerves, microbes or microbial products, immune cells, and tumor cells may occur in selected cancers.We identify causal examples in which neural signals alter microbial behavior or stress-dependent microbial metabolic changes are required for tumor-promoting outputs, and we distinguish evidence for convergence from formal non-additive synergy. We further propose the Tumor Neuromicrobiome Signature (TNS) as a testable research framework and specify analytical feasibility criteria, contamination safeguards, cross-scale data harmonization, confidence-aware subtyping, and a closed-loop workflow for longitudinal clinical testing. Finally, we review mechanism-matched neural, microbial, metabolic, and immune interventions while emphasizing that intratumoral microbial viability remains controversial, that the framework remains robust through the gut–system–tumor axis if local microbial evidence is weakened, and that prospective causal and clinical utility validation is required before routine use.