Aug 2026· Chinese Medical Journal· 0 citations· 304 references
Medicine
TL;DR
This review systematically elaborates on the central role of "tumor-host" metabolic crosstalk in reshaping both the TME and the broader host macroenvironment, suggesting the need for multiscale metabolic interventions to improve cancer treatment efficacy.
Abstract
ABSTRACT
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.
This review comprehensively examines the cellular and acellular architecture of the TME, emphasizing its spatial organization, metabolic reprogramming, mechanical properties, and immunological regulation across diverse tumor types.
R. Latif, Taufiq Nawaz· Critical reviews in oncology...· 0 citations
Current insights into the molecular mechanisms underlying TME remodeling are summarized, including ECM mechanotransduction, hypoxia-driven signaling, hypoxia-driven signaling, epigenetic regulation, metabolic reprogramming, and extracellular vesicle-mediated communication.
Xiaoying Li, Shuang Dai, Dan Cao et al.· Frontiers in Cell and Develo...· 0 citations
Emerging evidence demonstrates that tumor metabolic reprogramming not only supports tumor-cell proliferation but also promotes the establishment of an immunosuppressive tumor microenvironment (TME) by altering nutrient competition and metabolite accumulation. Therefore, metabolic reprogramming and immune evasion should be regarded as closely interconnected processes rather than independent phenotypes. By altering the metabolite composition of the TME and local metabolic programs, tumor metabolic reprogramming suppresses immune activation and shapes immune-cell function and fate, thereby promoting cancer immune evasion. This review focuses on two mechanistically developed axes linking tumor metabolism to immune suppression: glycolysis-associated lactate accumulation and lactylation, and nutrient competition involving amino acids and lipids. We summarize how lactate acts as both a metabolic substrate and signaling mediator, how lactylation translates metabolic changes into epigenetic regulation of immune-related transcriptional programs, and how depletion of glutamine, tryptophan, and arginine, together with lipid accumulation and remodeling, impairs effector-cell metabolic fitness while favoring regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. We further examine hypoxia as a contextual amplifier, the immune-evasion outcomes and reciprocal feedback circuits produced by these alterations, and therapeutic strategies targeting the metabolism–immunity axis. Particular attention is given to context-dependent effects and evidence maturity, because lactate-, hypoxia-, and metabolite-associated pathways are not uniformly immunosuppressive across cell types and conditions. Although preclinical findings support interventions targeting lactate production or transport, lactylation-associated regulators, amino acid metabolism, and the ecto-5′-nucleotidase (CD73)–adenosine axis, clinical evidence remains limited and heterogeneous. Biomarker-guided patient selection, confirmation of target engagement, preservation of immune-cell metabolic fitness, and rational combination strategies will be essential for clinical translation.
Hailun Wang, Han-Yuan Zhao, Xuelu Pu et al.· Frontiers in Oncology· 0 citations
Metabolic reprogramming constitutes a fundamental hallmark of malignancy, orchestrating a hostile tumor microenvironment (TME) that severely compromises anti-tumor immunity. Despite the transformative success of immune checkpoint blockade and adoptive cell therapies, clinical efficacy is frequently curtailed by the metabolic barriers imposed by the TME. This review systematically elucidates the complex metabolic interplay between tumor cells and infiltrating T cells, highlighting two defining mechanisms driving immune evasion: the competitive sequestration of essential nutrients and the accumulation of immunosuppressive oncometabolites. We detail how the depletion of glucose and critical amino acids (glutamine, arginine, methionine, etc.) imposes a state of “metabolic siege” on T cells, impairing their bioenergetics and effector functions. Concurrently, we explore how accumulated metabolites—such as lactate, succinate, 2-hydroxyglutarate, kynurenine, and lipids—function as non-canonical signaling molecules to subvert immune surveillance via epigenetic remodeling and oxidative stress. Furthermore, we synthesize emerging therapeutic strategies designed to dismantle this metabolic barrier, including targeting metabolic enzymes (IDO1 and FASN) and transporters, repurposing metabolic waste, and genetically engineering T cells with enhanced metabolic fitness and resilience. By integrating the latest insights into the “metabolism–epigenetics–immunity” axis, this review provides a theoretical foundation for developing next-generation immunotherapies that target metabolic vulnerabilities to overcome resistance in cancer treatment.
Jia-Ning Zhang, Zi-Mei Tang, Yiran Wang et al.· Cells· 0 citations
Metabolic reprogramming is a fundamental regulator of immune cell fate and function in the tumor microenvironment (TME), though the relative contributions of individual metabolic pathways vary across immune cell subsets, tumor types, and disease stages. Competition for nutrients, hypoxia, and the accumulation of immunosuppressive metabolites reshape the TME's metabolic landscape, driving functional exhaustion of antitumor immune cells while promoting the persistence of immunosuppressive populations. These metabolic adaptations have emerged as critical determinants of immune evasion, therapeutic resistance, and responses to cancer immunotherapy. In this review, we examine immune cell metabolism from four complementary perspectives: the physiological metabolic programs of major immune cell populations and their remodeling within the TME; the functional consequences of metabolic reprogramming for antitumor immunity; the principal metabolic drivers, including hypoxia, nutrient competition, and suppressive metabolites; and current therapeutic strategies targeting key immunometabolic pathways, with particular emphasis on glutamine, fatty acid, and lactate metabolism. We further discuss emerging metabolic modulators, their interactions with immune checkpoint blockade, and the opportunities and limitations of combining metabolic intervention with established cancer therapies. Finally, we highlight major translational challenges, including metabolic heterogeneity, limited clinical validation, biomarker identification, and the need for standardized metabolomic and single-cell approaches to enable precision immunometabolism. A more comprehensive understanding of immune cell metabolic regulation may facilitate the development of biomarker-guided therapeutic strategies that selectively restore antitumor immunity while minimizing systemic toxicity, thereby advancing the next generation of personalized cancer immunotherapies.
Yi-Qing Jiang, Yan-Ling Wu, Tian-Lei Ying· Cancer Biome and Targeted Th...· 0 citations
This review clarifies the metabolic crosstalk mechanisms between ECM, CAFs and tumor cells, providing a theoretical basis for developing combinatorial therapeutic designs integrating metabolism-targeted agents, stroma-directed therapies and immunotherapy to amplify anti-tumor efficacy.
Chen-Yu Wei, Hao-Lin Sun, Jiang-Lan Long et al.· International Immunopharmaco...· 0 citations
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