Abstract

Genomic instability is a defining feature of cancer progression and therapeutic resistance, yet contemporary oncology interprets it largely through tumor-intrinsic genetic alterations, with less attention to the evolving host physiological context in which DNA damage accumulates and genome maintenance operates. In this perspective, we propose a longitudinal host-transfer-state framework that treats host physiology not as a static background but as a continuously evolving adaptive system. Gut microbial ecology, micronutrient physiology, inflammatory signaling, circadian organization, hydration, environmental exposures, and chronic stress are framed as interacting biologic transfer systems that shape DNA repair fidelity, oxidative buffering, immune coordination, and adaptive tumor behavior over time. These influences are proposed to vary by tumor type, treatment context, and individual physiologic reserve, and clinically observable disease may lag behind deeper latent biologic dynamics. We further outline how longitudinal multi-omic integration and constrained, bounded artificial intelligence—used for longitudinal data integration, normalization, contextualization, and bounded analytical support rather than autonomous decision-making—could identify patient-specific constraints on genome maintenance and treatment tolerance. Host-directed strategies are presented as complementary to, not replacements for, established tumor-directed therapies.

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