Endocannabinoid System Dysregulation as a Meta-Hallmark of Cancer: A Systems-Level Failure of Biological Coordination

Cancer is increasingly understood as a systems-level disease characterised by failures of coordination, resolution, and recoverability, rather than isolated genetic defects alone. While hallmark frameworks describe recurrent behavioural features of malignancy, they do not fully explain why these features stabilise, cluster, recur, and resist durable correction across diverse tumour types and treatment contexts. This paper proposes that chronic dysregulation of the Endocannabinoid System (ECS) constitutes a meta-hallmark of cancer: a regulatory failure operating upstream of established hallmark processes. The ECS is a conserved, system-wide governance network integrating immune tone, inflammatory resolution, metabolic regulation, stress adaptation, temporal coordination, and neuro-immune communication. Impairment of ECS tone, timing, and feedback control is argued to create a permissive biological terrain in which multiple cancer hallmarks emerge, interact, and persist. Using an expanded 26-axis hallmark ontology, this work maps ECS dysregulation across genomic, metabolic, immune, microenvironmental, and phenotypic domains, and positions programmed cell death pathways as execution-level decision processes biased by upstream regulatory context rather than isolated pathway defects. In doing so, cancer is reframed as a failure of biological governance and recoverability, not merely unchecked cellular proliferation. Recognising ECS dysregulation as a foundational regulatory failure has implications