Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Characteristics of the Tumor Microenvironment That Influence Immune Cell Functions: Hypoxia, Oxidative Stress, Metabolic Alterations

Augustin, Ryan C. and Delgoffe, Greg M. and Najjar, Yana G. (2020) Characteristics of the Tumor Microenvironment That Influence Immune Cell Functions: Hypoxia, Oxidative Stress, Metabolic Alterations. Cancers, 12 (12). p. 3802. ISSN 2072-6694

Published Version

Download (638kB) | Preview


Immunotherapy (IMT) is now a core component of cancer treatment, however, many patients do not respond to these novel therapies. Investigating the resistance mechanisms behind this differential response is now a critical area of research. Immune-based therapies, particularly immune checkpoint inhibitors (ICI), rely on a robust infiltration of T-cells into the tumor microenvironment (TME) for an effective response. While early efforts relied on quantifying tumor infiltrating lymphocytes (TIL) in the TME, characterizing the functional quality and degree of TIL exhaustion correlates more strongly with ICI response. Even with sufficient TME infiltration, immune cells face a harsh metabolic environment that can significantly impair effector function. These tumor-mediated metabolic perturbations include hypoxia, oxidative stress, and metabolites of cellular energetics. Primarily through HIF-1-dependent processes, hypoxia invokes an immunosuppressive phenotype via altered molecular markers, immune cell trafficking, and angiogenesis. Additionally, oxidative stress can promote lipid peroxidation, ER stress, and Treg dysfunction, all associated with immune dysregulation. Finally, the metabolic byproducts of lipids, amino acids, glucose, and cellular energetics are associated with immunosuppression and ICI resistance. This review will explore these biochemical pathways linked to immune cell dysfunction in the TME and highlight potential adjunctive therapies to be used alongside current IMT.


Social Networking:
Share |


Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Augustin, Ryan C.augustin@pitt.eduaugustin
Delgoffe, Greg M.gmd34@pitt.edugmd34
Najjar, Yana G.yan7@pitt.eduyan7
Date: 17 December 2020
Date Type: Publication
Journal or Publication Title: Cancers
Volume: 12
Number: 12
Publisher: MDPI AG
Page Range: p. 3802
DOI or Unique Handle: 10.3390/cancers12123802
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
Uncontrolled Keywords: immunometabolism, immunotherapy, cellular energetics
ISSN: 2072-6694
Official URL:
Article Type: Review
Date Deposited: 04 Jun 2021 17:22
Last Modified: 04 Jun 2021 17:22


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item