Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy

Sep 21, 2026

Uploaded by Oliver

Metabolic reprogramming is a central feature of tumors, arising under hypoxia and nutrient deficiency and driving shifts from oxidative phosphorylation to aerobic glycolysis, the Warburg effect, and downstream lactate acidification, altered lipid synthesis, and glutaminolysis. Within the tumor immune microenvironment, these changes support tumor immune evasion by coordinating suppressive interactions between cancer and immune cells. Colorectal cancer shows abnormal glycolysis, glutaminolysis, and lipid synthesis, where acidosis and nutrient shortage restrain anti-tumor immunity while promoting Tregs and M2-like macrophages. The review summarizes mechanisms, including GPR81/PD-L1 signaling, genetic/epigenetic influences, and microbiota effects, and discusses emerging immunotherapy strategies.

LanguageEnglish

CategoryResearch & Report

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Pages21

Reading Time53 min

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Introduction

Metabolic reprogramming in the TME

TYPE Review PUBLISHED 25 July 2024 DOI 10.3389/fimmu.2024.1353787 OPEN ACCESS EDITED BY Elisa Giovannetti, VU Medical Center, Netherlands REVIEWED BY Hongfei Jiang, Qingdao University, China Sweta Ghosh, University of Louisville, United States *CORRESPONDENCE Andrea Nicolini [andrea.nicolini@med.unipi.it](andrea.nicolini@med.unipi.it)[ ](andrea.nicolini@med.unipi.it)†Retired RECEIVED 11 December 2023 ACCEPTED 04 March 2024 PUBLISHED 25 July 2024 CITATION Nicolini A and Ferrari P (2024) Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy. Front. Immunol. 15:1353787 . doi: 10.3389/fimmu.2024.1353787 COPYRIGHT © 2024 Nicolini and Ferrari. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy Andrea Nicolini 1*† and Paola Ferrari 2 1 Department of Oncology, Transplantations and New Technologies in Medicine, University of Pisa, Pisa, Italy, 2 Unit of Oncology, Department of Medical and Oncological Area, Azienda OspedalieraUniversitaria Pisana, Pisa, Italy Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deﬁciency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidiﬁcation, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME) . The growing interest in the metabolic reprogramming of the TME, particularly its signiﬁcance in colorectal cancer (CRC)—one of the most prevalent cancers—has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deﬁciency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, signiﬁcantly inﬂuence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1a) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efﬁcacy of immunotherapy. KEYWORDS metabolic reprogramming, colorectal cancer, tumor immune microenvironment, tumor immune escape, immunotherapy Frontiers in Immunology 01 [frontiersin.org](frontiersin.org) Introduction Preventi

FAQs

How does metabolic reprogramming in colorectal cancer contribute to tumor immune escape?

Metabolic shifts promote an immunosuppressive tumor immune microenvironment by altering lactate levels, acidity, lipid synthesis, and glutaminolysis, which reduce anti-tumor immune functions and enable cancer–immune cooperation that favors escape.

What microenvironment conditions in the TME are linked to metabolic reprogramming?

The TME is characterized by high oxygen consumption and lactate export via aerobic glycolysis, leading to extracellular acidification and hypoxia, both of which influence immune cell activity.

Which mechanisms described in CRC affect immune checkpoint pathway activity and antigen presentation?

Activation of GPR81 signaling in CRC increases PD-L1 expression and reduces dendritic cell antigen presentation capability, weakening anti-tumor immune responses.

Sep 21, 2026

Uploaded by Oliver