Tumor-host metabolic interactions in the microenvironment and macroenvironment: Mechanisms and targeting strategies

Tumor metabolic reprogramming is a hallmark of cancer and is driven not only by intrinsic mechanisms of tumor cells but also by dynamic interactions between the local tumor microenvironment (TME) and the host macroenvironment. This review systematically elaborates on the central role of "tumor-host" metabolic crosstalk in reshaping both the TME and the broader host macroenvironment. In the TME, hypoxia, nutrient deprivation, metabolic waste accumulation, and metabolic interactions among immune and stromal cells collectively facilitate tumor adaptation to harsh conditions and drive tumor progression. Concurrently, host macroenvironmental factors, including the gut microbiota and its metabolites, adipose tissue, systemic chronic inflammation, and hormonal imbalances, remotely regulate tumor initiation and development through multiple mechanisms. We further summarize emerging therapeutic strategies targeting metabolic pathways and emphasize the future need to break down boundaries between microenvironments and macroenvironments, suggesting the need for multiscale metabolic interventions to improve cancer treatment efficacy.