Tumor microenvironment and macroenvironment: A new perspective on holistic oncology.

The tumor microenvironment (TME) and tumor macroenvironment (TMaE) jointly shape cancer biology by linking local cellular niches with systemic host physiology. The TME provides the immediate soil for tumor initiation, progression, and therapy resistance, whereas the TMaE integrates metabolic, immune, neuroendocrine, microbial, and inflammatory signals that remodel local ecosystems. Recent advances highlight how systemic factors, including aging, energy imbalance, chronic inflammation, cachexia, and psychosocial stress, interact with extracellular matrix remodeling, vascular dynamics, and immune surveillance to influence tumor dormancy, metastatic reactivation, and therapeutic outcomes. However, the conceptual boundaries between TME and TMaE remain unclear, mechanistic insights are limited, and current models insufficiently capture local-systemic crosstalk. Future strategies integrating multi-omics, advanced imaging, and humanized models are essential to map this multidimensional interplay. A deeper understanding of TME-TMaE will be critical to refine precision oncology, advance preventive strategies, and design combinatorial therapies targeting both local and systemic cancer ecosystems. This review highlights the roles of the TME and TMaE in tumor initiation, progression, and heterogeneity, their interactions, and the clinical implications for classification, therapy, and prognosis.