Metabolic reprogramming is a central hallmark of tumor development and progression. A recent review, “Tumor–host metabolic interactions in the microenvironment and macroenvironment: Mechanisms and targeting strategies,” published in the Chinese Medical Journal, systematically elucidates the interconnected and dynamic interplay between the tumor microenvironment (TME) and the tumor macroenvironment. This review highlights how these two systems collectively regulate metabolic reprogramming in tumor cells, influencing tumor survival, progression, and immune evasion, thereby offering a novel perspective on systemic metabolic regulation in cancer (Figure 1). The review was made available online on August 24, 2026, in the Chinese Medical Journal
Traditional cancer metabolism research has largely focused on the TME. However, this review emphasizes that a microenvironment-only view is insufficient to fully capture tumor complexity. The authors introduce the concept of the “tumor macroenvironment,” framing the tumor as an entity shaped by systemic host factors. The article summarizes the topic from two perspectives: 1. Microenvironment. This includes the physical microenvironment (hypoxia and nutrient deprivation) and the social microenvironment (immune cells and cancer-associated fibroblasts). 2. Macroenvironment. This covers the gut microbiota, adipose tissue, systemic inflammation, and hormonal imbalances. By describing how the micro- and macroenvironments drive tumor progression through metabolic reprogramming, the article builds a bridge between these two systems and, on this basis, proposes potential novel targeted therapeutic strategies.
At the TME level, the article describes how tumor cells adapt their glucose, lipid, and amino acid metabolism to survive under hypoxic and nutrient-deprived conditions. It underscores the critical role of “metabolic waste products,” such as lactate and ammonia, in reshaping the immunosuppressive microenvironment. Furthermore, the review systematically summarizes the complex, often paradoxical, roles of tumor-associated macrophages, T cells, neutrophils, NK cells, and cancer-associated fibroblasts in metabolic competition and collaboration with tumor cells. This reveals the central function of metabolic checkpoints in regulating antitumor immunity (Figure 2).
Extending beyond the microenvironment, the review broadens its scope to the host systemic macroenvironment. It focuses on the regulatory effects of the gut microbiota on distant tumors via pathways such as the “gut–liver axis” and “gut–brain axis.” The article also systematically summarizes how exercise, dietary patterns, and aging remodel the gut microbiota and adipose tissue, thereby altering systemic inflammation and hormonal balance. This creates a systemic environment that can either promote or inhibit tumor development and progression (Figure 3).
Based on this complex interactive network, the review summarizes emerging precision therapeutic strategies targeting metabolism. These include: nanotechnology-based depletion of pro-tumor macrophages, investigating the anticancer mechanisms of active ingredients in traditional Chinese medicine, drug repurposing, and combination therapies to overcome resistance. Notably, it introduces innovative approaches such as genetically engineered adipocytes, specific probiotics, and exercise-induced factors, to reshape the host macroenvironment, compete with tumors for nutrients, or enhance immune surveillance.
In conclusion, this review transcends the traditional TME-centric view by constructing a comprehensive “tumor–host” metabolic interaction map at both local and systemic scales. The authors emphasize that future cancer therapy must integrate the micro- and macroenvironment, advocating for multi-scale metabolic interventions—such as combining exercise and dietary modifications—to develop more effective, holistic treatment strategies. This work not only provides a new framework for understanding the systemic nature of cancer but also identifies promising directions for clinical translational research.
Reference
Title of original paper: Tumor–host metabolic interactions in the microenvironment and macroenvironment: Mechanisms and targeting strategies
Journal: Chinese Medical Journal
DOI: https://doi.org/10.1097/CM9.0000000000004174
About Linchong Sun from Guangdong Provincial People’s Hospital/Southern Medical University
Linchong Sun is a Professor, Guangdong Provincial People’s Hospital/Southern Medical University, engaged in the crosstalk between the tumor microenvironment (micro- and macroenvironments) and metabolism. He has published academic papers in journals such as Cell Metabolism, Nature Cancer, Nature Chemical Biology, EMBO Journal, and Cell Research.
Caixia Suo is an Associate Professor, Second Affiliated Hospital of South China University of Technology/Guangzhou First People’s Hospital, mainly engaged in research on tumor immunology and tumor metabolism, and has published academic papers in journals such as Cell Metabolism, Nature Chemical Biology, Nature Communications, and EMBO Reports.
Yi Zhang is a doctoral student at the Guangdong Provincial People's Hospital/Southern Medical University.
Funding information
This work was supported by grants from the National Natural Science Foundation of China (Grant No. 82422057 and 82273221 for L.S., 82573034 and 82203556 for C.S.), National Science and Technology Major Project (2025ZD0545500, 2025ZD0545504 for L.S.), the Tianfu Jincheng Laboratory (No. TFJCPI20250001 for L.S.), Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120 for L.S.), and the Basic Funding of Guangzhou Municipal Science and Technology Bureau (Grant No. 2024A04J6493 for L.S.).
Chinese Medical Journal
Literature review
Not applicable
Tumor–host metabolic interactions in the microenvironment and macroenvironment: Mechanisms and targeting strategies
24-Aug-2026
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