Tumors evolve within complex, adaptive ecosystems that operate across spatial, temporal, and systemic scales. Within each tumor microenvironment, numerous diverse cell populations assemble into specialized niches that are continually shaped by systemic physiology, environmental inputs, and therapeutic pressure. Beyond the local microenvironment, cancer progression is governed by the host macroenvironment, where intrinsic biological determinants intersect with modifiable factors to collectively impact physiological fitness and tissue resilience. Here, we propose a multi-scale framework that unites tumor biology with organismal physiology and reframes therapy from eliminating malignant cells in isolation to reprogramming the cellular, vascular, and systemic networks that sustain disease. We highlight emerging approaches that aim to restore physiological equilibrium, spanning from spatial multi-omics and AI-driven pathology to immune-vascular normalization and physiological conditioning. Together, these dimensions define an integrative vision for precision oncology that bridges discovery and intervention to achieve durable and ultimately curative cancer therapy.
Quail et al. (2026) studied this question.