Despite the tumor microenvironment (TME) being a major therapeutic focus, the clinical translation of TME-targeted agents has been largely unsuccessful, a paradox that challenges paradigms rooted in a reductionist view of the TME as a self-contained entity. We propose a framework redefining the TME as an open, multi-scalar ecosystem dynamically shaped by systemic host factors. Locally, cancer-associated fibroblasts (CAFs), myeloid cells and the vasculature act not as isolated cell types but as integrated components of functional niches that orchestrate fibrosis, immunosuppression and angiogenesis. Systemically, the gut microbiome and chronic inflammation of ageing (‘inflammaging’) pre-condition the host terrain and modulate therapeutic responses across this network. Viewed through this systemic lens, resistance emerges not as molecular bypass but as ecological adaptation of a complex, open system. We argue that next-generation therapies will depend on spatial omics to map pathological niches and on rational, multimodal strategies that explicitly target the TME as a systemically integrated network.