Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Aug 29;10(1):66.
doi: 10.1186/s40364-022-00412-1.

Impact of NSCLC metabolic remodeling on immunotherapy effectiveness

Lulu Lv #  1 , Ruo Han Huang #  1 , Jiale Li  1 , Jing Xu  2 , Wen Gao  3
Affiliations
Review

Impact of NSCLC metabolic remodeling on immunotherapy effectiveness

Lulu Lv et al. Biomark Res. .

Abstract

It is known that metabolic reprogramming (MR) contributes to tumorigenesis through the activation of processes that support survival of cells, proliferation, and grow in the tumor microenvironment. In order to keep the tumor proliferating at a high rate, metabolic pathways must be upregulated, and tumor metabolism must be adapted to meet this requirement. Additionally, immune cells engage in metabolic remodeling to maintain body and self-health. With the advent of immunotherapy, the fate of individuals suffering from non-small cell lung cancer (NSCLC) has been transformed dramatically. MR may have a profound influence on their prognosis. The aim of this review is to summarize current research advancements in metabolic reprogramming and their impact on immunotherapy in NSCLC. Moreover, we talk about promising approaches targeting and manipulating metabolic pathways to improve cancer immunotherapy's effectiveness in NSCLC.

Keywords: Immunotherapy; Metabolic reprogramming; NSCLC; TME.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Metabolic control of glucose by cancer cells. Mitochondria are primarily involved in glycosis and the TCA cycle in glucose metabolism. The pathways in tumor cells are generally altered compared to those of normal cells. Figure created using BioRender.com
Fig. 2
Fig. 2
Reprogramming the metabolic process of glucose in lung cancer. In addition to HIF-1α pathway，PPARy and PI3K/AKT/mTOR signaling impair the activity of enzymes and transporters limiting metabolic reprogramming in NSCLC. In the cell, glucose is transported by glucose transporters (GLUT)1 and 4. Glycolysis begins with the phosphorylation of glucose by hexokinase (HK). In the cycle of pentose phosphate (PPP), glucose-6-phosphate is converted into nucleosides and NADPH by glucose-6-phosphate dehydrogenase (G6PD). Dephosphorylating PEP is accomplished by pyruvate kinase (PK) at the end of the glycolytic pathway to synthesize pyruvate and ATP. After that, pyruvate is turned into lactate by-lactate dehydrogenase (LDH). Lactate is delivered to the outside of the cell by monocarboxylate transporters (MCT) 1 and 4. During metabolism, pyruvate can be converted into acetyl coenzyme A (acetyl-CoA), which is following used by the tricarboxylic acid cycle in mitochondria to give rise to ATP and intermediate molecules that are essential to the biosynthesis of both lipids and amino acids. Figure created using BioRender.com
Fig. 3
Fig. 3
Aspects of glucose metabolism that may serve as therapeutic targets. A Cancer patients have successfully used immune-based interventions, including immune checkpoint inhibitors, to treat a variety of cancers. Low glucose, acidity and lactic acid in tumor microenvironment lead to enhanced expression of checkpoint receptors. In turn, this results in reduced glycosis and increased FAO, therefore causing immunosuppression. Immunotherapy targeted at these checkpoint receptors has been successful in restoring glycolysis to immune cells, which promotes anti-tumor immunity against tumors. B In the TME, increasing lactate promotes the survival of immune suppressive T cells and restraing the function of T effector. Lactate accumulation can be reduced by inhibiting lactate-producing enzymes, inhibiting lactate transporters or neutralizing acid-induced by lactic acid. These strategies have been proven effective in improving anti-tumor immunity. Figure created using BioRender.com
Fig. 4
Fig. 4
The effects of lung cancer metabolism on immune cells within the tumor microenvironment (TME). Cancerous TME develop in lungs, lacking glucose and tryptophan, while immune-suppressive molecules such as lactate and kynurenine accumulate. In the tumor microenvironment, the high levels of lactate inhibit the tumor immune responses by (1) polarizing macrophages toward the suppressive M2 phenotypes, as well as (2) preventing monocyte migration and dendritic cell differentiation. (3) The presence of excessive lactate also inhibits the function of CD8+ T cell directly. Besides kynurenine, tumors are also known to repress T-cell activity, as is tumor-induced tryptophan deficiency and glucose deprivation. Figure created using BioRender.com
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. - PubMed
    1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33. doi: 10.3322/caac.21654. - DOI - PubMed
    1. Gridelli C, Rossi A, Carbone DP, Guarize J, Karachaliou N, Mok T, et al. Non-small-cell lung cancer. Nat Rev Dis Primers. 2015;21(1):15009. doi: 10.1038/nrdp.2015.9. - DOI - PubMed
    1. Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet. 2021;398(10299):535–554. doi: 10.1016/S0140-6736(21)00312-3. - DOI - PubMed
    1. Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ, Jr, Wu YL, et al. Lung cancer: current therapies and new targeted treatments. Lancet. 2017;389(10066):299–311. doi: 10.1016/S0140-6736(16)30958-8. - DOI - PubMed

LinkOut - more resources