Metabolic licensing and restriction of innate immunity in the tumor microenvironment.

Authors

Ji Min Shin, Hye Yeon Choi, Jihyoun Kim, Seon Ah Lim

Published in

Frontiers in immunology. Volume 17. Pages 1935435. Epub Sep 16, 2026.

Abstract

Tumor progression is driven by metabolic remodeling that generates a microenvironment characterized by nutrient deprivation, hypoxia, lactate accumulation, lipid dysregulation, and oxidative stress. These conditions affect innate immune populations, including natural killer (NK) cells, dendritic cells (DCs), macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs), shaping their activation, persistence, and functional states. Although many studies have defined metabolic pathways that regulate innate immune function in cancer, these findings are often discussed at the level of individual pathways or individual cell types, obscuring shared principles by which the tumor microenvironment controls innate immunity. Here, we use the concepts of metabolic licensing and metabolic restriction to describe how metabolic capacity and environmental constraints interact to shape innate immune function. Metabolic licensing refers to context-dependent metabolic states that provide sufficient bioenergetic and biosynthetic capacity to support sustained antitumor effector function, whereas metabolic restriction describes conditions in which nutrient limitation, mitochondrial dysfunction, redox imbalance, or suppressive metabolites constrain or progressively erode these functions. Rather than representing fixed binary states, licensing and restriction can occur along a continuum shaped by cell identity, signal duration, and local tumor conditions. We discuss how metabolic licensing and restriction shape antitumor and immunosuppressive innate immune populations, examine the stress-sensing pathways that connect environmental cues to innate immune fate, and summarize therapeutic strategies aimed at restoring metabolic fitness or alleviating metabolic restriction. Considering innate immune responses in terms of metabolic licensing and restriction helps explain how shared metabolic pressures within tumors can impair effector cells while supporting suppressive innate populations and may inform the development of immunometabolic approaches to cancer therapy.

PMID:
42820105
Bibliographic data and abstract were imported from PubMed on 02 Oct 2026.

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