The niche-metabolism axis: reprogramming tumor-associated macrophages for precision immunotherapy

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.