Targeting myeloid cell plasticity and metabolic reprogramming to alleviate T cell dysfunction and exhaustion-associated states and enhance immune checkpoint blockade therapy.

Authors

Mingxing Wang, Jian Chen, Zhonghua Wu, Zhiying Wang, Zhixian Zhong, Yi Zhong

Published in

Biomarker research. Volume 14. Issue 1. Oct 16, 2026. Epub Oct 16, 2026.

Abstract

Immune checkpoint blockade (ICB) therapy has achieved clinical progress in various malignancies, yet primary and acquired resistance limits its efficacy in solid tumors. Myeloid cells in the tumor microenvironment (TME), including tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs), undergo metabolic reprogramming under hypoxia and nutrient stress. They impair effector T cell function and may contribute to exhaustion-associated states via nutrient competition, release of toxic metabolites, and formation of physical barriers, representing a critical resistance mechanism. This review summarizes the spatiotemporal heterogeneity of myeloid cells and the metabolic networks underlying their immunosuppressive phenotypes, focusing on dysregulated lipid and cholesterol metabolism, amino acid remodeling, the glycolytic switch, and subcellular stress responses. We analyze how metabolic dysregulation causes T cell dysfunction and, in defined contexts, contributes to exhaustion-associated transcriptional programs through nutrient competition, toxic metabolite accumulation, and upregulation of inhibitory receptor ligands, and summarize intervention strategies targeting myeloid recruitment, phenotypic remodeling, metabolic reprogramming, and pathological structures combined with ICB. We discuss challenges of efficacy heterogeneity and safety in clinical translation, and highlight the prospects of multi-omics and computational biology in guiding next-generation combination immunotherapy. Understanding myeloid metabolic plasticity may provide a basis for overcoming immunotherapy resistance and establishing precise synergistic strategies.

PMID:
42888442
Bibliographic data and abstract were imported from PubMed on 17 Oct 2026.

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