The hallmarks of neuro-immune reprogramming in cancer

Cancer immunity is commonly interpreted through tumor-centric and immune-intrinsic frameworks centered on antigenicity, immune checkpoint signaling, stromal architecture, and local immunosuppression within the tumor microenvironment. Although these models explain major determinants of immune surveillance and therapeutic response, they do not fully account for the marked heterogeneity in antitumor immunity observed across tumor types and among patients with apparently similar immunological features. Emerging evidence indicates that immune competence is also shaped by host-level regulatory systems, particularly neural and neuroendocrine pathways. Here, we propose the hallmarks of neuro-immune reprogramming in cancer as a conceptual framework to organize recurrent and analytically distinguishable modes through which neural circuits interact with tumor-, stromal-, and immune-intrinsic processes to influence antitumor immunity across its initiation, tissue access, metabolic sustainability, temporal coordination, and persistence. These hallmarks include neural calibration of innate immune set points, neurogenic control of antigen presentation and immune priming, neural gating of immune cell trafficking and tissue access, neuroendocrine constraint of immune metabolic fitness, circadian-neural orchestration of immune timing, neural imprinting of durable immunosuppressive bias, and neuro-immune-tumor circuit reinforcement. Importantly, the evidentiary maturity supporting these hallmarks is not uniform: some are supported by direct cancer-relevant mechanistic studies, whereas others currently remain best understood as cross-disciplinary inferences or testable conceptual extensions. Together, this framework positions neuro-immune regulation as an under integrated systems-level determinant of immune heterogeneity, therapeutic responsiveness, and resistance in cancer, and provides a foundation for mechanistic investigation, biomarker development, and neural-informed immunotherapeutic strategies.