Aug 2026· Trends in Molecular Medicine· 0 citations· 105 references
Medicine
TL;DR
This framework highlights that therapeutic paradigms should shift from nonselective TAM depletion to niche-specific metabolic-epigenetic reconstruction, providing a precise roadmap for designing next-generation engineered macrophage therapies.
Abstract
Tumor-associated macrophages (TAMs) critically modulate solid tumor progression and immunotherapy resistance, yet their profound context-dependent heterogeneity defies the traditional M1/M2 dichotomy. In this review, we propose the 'niche-metabolism axis' framework, deconstructing the tumor microenvironment into dynamically interacting functional niches (e.g., hypoxic cores and tertiary lymphoid structures). Within these niches, specific physicochemical stresses substantially influence localized TAM metabolic reprogramming. Metabolites such as lactate and lipids act not merely as substrates but as signaling mediators and epigenetic donors, shaping TAM phenotypes. Consequently, TAMs acquire spatial metabolic imprints and evolve into 'ecosystem engineers' that actively remodel the immune microenvironment. This framework highlights that therapeutic paradigms should shift from nonselective TAM depletion to niche-specific metabolic-epigenetic reconstruction, providing a precise roadmap for designing next-generation engineered macrophage therapies.
A context-dependent state-transition model is proposed in which pressures are decoded by interconnected nutrient- and stress-sensing pathways, integrated through mitochondrial bioenergetic and redox adaptation, and translated by metabolite-dependent chromatin remodeling into persistent TAM functional programs that cons...
Jing-Hao Pan, Bo-Yang Li, Lucy Yue Lau et al.· Biochimica et biophysica act...· 0 citations
The metabolic supply-demand mismatch explains why certain interventions can revive effector cells while potentially harming other cell types, and the need for spatially resolved metabolic profiling, biomarker-driven patient stratification, and personalized therapies to overcome metabolic immunosuppression and improve c...
Xiang-Yang Wang, Ying Wu, Yu-Tong Fu et al.· Oncology Research· 0 citations
Tumor metabolic reprogramming serves as a fundamental driver of malignancy, fueling cancer cell growth while reshaping the immune landscape through metabolite accumulation. Ferroptosis, an iron-dependent form of regulated cell death, is intricately linked to these metabolic shifts. In the tumor microenvironment, tumor-...
Hu-Chen Hu, Yue-Qi Ma· Journal of Cancer Metastasis...· 0 citations
Tumor-associated macrophages (TAMs) play a pivotal role in tumor progression and immune evasion, with recent evidence indicating that metabolic reprogramming is crucial in determining their functional phenotype. Alterations in glucose, amino acid, and lipid metabolism are central to the regulation of TAMs plasticity,...
Wei-Feng Yuan, Yi-Ran Zhu, Yu-Xin Zhang et al.· Journal of Translational Med...· 0 citations
This chapter provides an integrated framework for understanding TAM biology across multiple regulatory dimensions, including ontogeny, plasticity, metabolism, epigenetic control, and spatial niche organization, and synthesizes current and emerging therapeutic strategies targeting TAM recruitment, survival, reprogrammin...
Atif Elnaggar, Abdelrahman Elnaggar· Advances in Cancer Research· 0 citations
Glioblastoma (GBM) remains one of the most lethal cancers, with recurrence in nearly all patients despite standard therapy. However, the biological mechanisms governing recurrence remain incompletely understood. Increasing evidence suggests that recurrence is driven not only by tumor-intrinsic resistance, but also by d...
Jian-Yu Lu, Rou-Xi Song, Wei Gao et al.· Biochimica et biophysica act...· 0 citations
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