Dynamic remodeling of amino acid metabolism in tumor-associated macrophages: Fueling immunosuppression, reshaping tumor niches, and unlocking metabolic checkpoints

Abstract

Background

Tumor-associated macrophages depend on their amino acid metabolism to determine their properties and immune function and play important roles in the tumor microenvironment (TME). Although in previous studies, targeting amino acid metabolism to transform the protumor function of tumor-associated macrophages (TAMs) into antitumor immune function has shown promising application as a tumor therapy, current clinical research is still limited. There is a lack of discussion on the mechanism and treatment strategy for determining tumor progression by controlling amino acid metabolism in TAMs, as does a summary of studies on promoting tumor progression by reshaping amino acid metabolism in TAMs.

Aim of review

This review aims to systematically review and summarize the crosstalk between amino acid metabolism in TAMs and the TME, analyze the determining role of its metabolic network in tumor occurrence and development, and summarize therapies on this basis to help determine the development status and emerging technologies in the field of amino acid metabolism in TAMs for tumor therapy.

Key scientific concepts of review

This review dissects how TAMs exploit amino acid dynamics via transporters, enzymes, and sensors to adopt protumoral phenotypes, depleting critical metabolites and crippling antitumor T-cell responses. We map the immunometabolic crosstalk through which TAMs reshape immunity, highlighting nutrient competition and metabolic byproducts as dual drivers of immune dysfunction. Emerging therapeutic strategies targeting these pathways (IFN-γ-JAK-STAT1 and IL-6/JAK2/STAT3) have been critically evaluated for their potential to reprogram TAMs and reverse immunosuppression. Key challenges, such as TAM heterogeneity, metabolic plasticity, and therapy resistance, are addressed, emphasizing the need for single-cell-resolution mapping of TAM metabolic states to identify context-dependent vulnerabilities. Finally, we advocate for combinatorial approaches that couple metabolic rewiring with immunotherapies, proposing that disrupting amino acid dependencies in TAMs could dismantle the immunosuppressive TME.