Related Experiment Video

Updated: Aug 8, 2026

Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells
09:04

Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells

Published on: March 7, 2025

Metabolic immune checkpoints in cancer: how tumor-derived metabolites shape immunotherapy resistance

Renjie Pan1, Dongdong Chen2, Yilu Wu3

  • 1Department of Clinical Laboratory, Xinghua People's Hospital Affiliated to Yangzhou University, Xinghua, Jiangsu, China.

Frontiers in Immunology
|August 7, 2026
PubMed

Insights

Tumor metabolites like lactate and adenosine create suppressive environments, hindering cancer immunotherapy effectiveness. Targeting these metabolic checkpoints alongside immune checkpoint blockade may improve treatment outcomes.

Area of Science:

  • Immunology
  • Cancer Biology
  • Metabolism

Background:

  • Immune checkpoint blockade (ICB) has revolutionized cancer therapy but faces intrinsic and acquired resistance.
  • Tumor microenvironment metabolic states, beyond PD-1/PD-L1/CTLA-4, significantly impact ICB failure.
  • Tumor-derived metabolites act as metabolic immune checkpoints, suppressing anti-tumor immunity.

Purpose of the Study:

  • To review evidence on how specific metabolites mediate immune escape and ICB resistance.
  • To explore the role of lactate, adenosine, tryptophan, and nucleotide metabolites in immunotherapy failure.
  • To discuss strategies for targeting metabolic checkpoints to enhance ICB efficacy.

Main Methods:

  • Mini-review of recent experimental evidence.
  • Analysis of metabolite functions in immune suppression within the tumor microenvironment.
  • Examination of specific metabolic pathways and their impact on immune cells (T cells, NK cells, macrophages) and immune checkpoints.

Main Results:

  • Lactate promotes regulatory T cells (Tregs), impairs T-cell function, and contributes to resistance.
  • The CD73-adenosine axis suppresses cytotoxic immune cells (CD8+ T cells, NK cells) and promotes suppressive immune cells.
  • Tryptophan metabolites (beyond IDO1) and nucleotide metabolites (UDP signaling) also drive immunosuppression and macrophage-mediated inhibition.

Conclusions:

  • Metabolic immune checkpoints are critical drivers of resistance to cancer immunotherapy.
  • Targeting metabolic pathways in combination with ICB offers a promising strategy to overcome resistance.
  • Understanding the spatial and cellular context of metabolite-mediated suppression is key for developing precise therapeutic interventions.
Keywords:
adenosineimmunotherapy resistancelactatemetabolic immune checkpointtryptophan metabolismtumor microenvironment

Related Concept Videos

Tumor Immunotherapy01:27

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
The Tumor Microenvironment02:17

The Tumor Microenvironment

Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
The Tumor Microenvironment02:17

The Tumor Microenvironment

Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...