Targeting Stress Response Pathways & Metabolic Vulnerabilities in Cancer

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Submission deadlines

  1. Manuscript Summary Submission Deadline 13 August 2025 | Manuscript Submission Deadline 1 December 2025

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Background

Cancer cells hijack key signaling pathways, including PI3K–AKT–mTORC1 and MYC, to fuel their rapid growth by increasing metabolic flux. In certain cancers, mutations, including loss-of-function mutations or neomorphic mutations in genes encoding enzymes like succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase (IDH1/IDH2), lead to the accumulation of metabolites such as succinate, fumarate, or a modified metabolite, for example, 2-hydroxyglutarate (2HG). These metabolites referred to as "oncometabolite" drive cancer progression by disrupting normal cellular metabolism. For example, IDH mutations convert α-ketoglutarate (α-KG) into d-2HG, disrupting the TCA cycle. Additionally, l-2HG, typically present at low levels, accumulates in response to hypoxia, acidic conditions, or dysfunctional mitochondrial activity, contributing to tumor aggressiveness in multiple cancers.

Targeting key metabolic pathways, such as glycolysis, oxidative phosphorylation, amino acid metabolism, and fatty acid oxidation, disrupts cancer cells' energy production and function. This makes them vulnerable to targeted inhibition, which can hinder tumor growth. Combining metabolic inhibitors with chemotherapy or immunotherapy shows promise in improving treatment effectiveness and overcoming resistance, offering a strategic approach to disrupt tumor metabolism.

Metabolism and reactive oxygen species (ROS) production are closely intertwined, as metabolic processes in cells generate ROS as byproducts, particularly during oxidative phosphorylation in the mitochondria. Cancer cells produce high levels of reactive oxygen species, including superoxide, hydrogen peroxide (H2O2), and lipid hydroperoxides (LOOH), primarily through the mitochondrial electron transport chain (ETC) and NADPH oxidases. H2O2, generated from superoxide, oxidizes cysteine residues in proteins, activating redox signaling pathways that promote tumor growth, survival, and invasion. Proteins such as PTEN and SHP2 are particularly vulnerable to this oxidative modification. To combat ROS damage, cancer cells activate NRF2, a transcription factor that regulates antioxidant defenses and supports pathways for NADPH and glutathione (GSH) production. Mutations in KEAP1 or NRF2 itself, common in cancers like non-small cell lung cancer (NSCLC), enhance tumor growth by boosting antioxidant activity. Interestingly, activation of NRF2 or antioxidant supplementation can also promote metastasis by stabilizing BACH1, a factor that drives metastasis. Additionally, many cancers increase expression of TIGAR, a protein that enhances antioxidant defenses by stimulating the oxidative pentose phosphate pathway (PPP) and NADPH production. Although the precise mechanism by which ROS regulates cancer stem cell traits remains unclear, growing evidence suggests that ROS plays a crucial role in the self-renewal and differentiation abilities of cancer stem cells.

Metals such as selenium, iron, and copper are essential for both ROS generation and the functioning of ETC and antioxidant enzymes, although their roles in cancer remain underexplored. Copper, for instance, can regulate autophagy and influence tumor growth. LOOH can induce ferroptosis, a form of cell death caused by lipid peroxidation, but cancer cells counteract this by utilizing systems like cysteine–glutathione (GSH)–GPX4 and CoQ10–FSP1, which convert LOOH into non-toxic lipid alcohols (LOH), preventing ferroptosis and promoting cancer cell survival.

Stress response pathways are vital for cancer cell survival and progression, allowing adaptation to harsh tumor conditions like nutrient deprivation, hypoxia, and oxidative stress. Mechanisms such as autophagy, the unfolded protein response (UPR), and DNA damage response help maintain homeostasis, repair damage, and support proliferation. These pathways enhance resilience, enabling cancer cells to withstand therapies causing relapse. Dysregulation of stress response mechanisms can promote tumor survival, metastasis, and therapy resistance, making them key targets for novel treatments aimed at disrupting tumor adaptation.

The goal of this issue is to investigate the role of ROS in cancer progression and therapeutic targeting, with an emphasis on developing combined strategies that target metabolic or stress response pathways. It will offer new insights into how metal homeostasis impacts cancer progression and metastasis, highlighting potential therapeutic targets, including metal-dependent enzymes and proteins. Additionally, the issue will explore therapeutic approaches to induce metal-dependent cell death pathways, including ferroptosis, cuproptosis, and pyroptosis in cancer cells or inhibit autophagy/mitophagy to overcome resistance mechanisms and promote tumor regression.

We welcome Original Research Papers, Reviews, Mini-Review Articles, Methodological Advancements, Clinical Trials, Systematic Reviews, Meta-analyses, Data Reports, and Case Reports of preclinical and clinical studies that include but are not limited to the following topics:

1) Targeting metabolic reprogramming
2) Targeting the Integrated Stress Response signaling pathway
3) Lipid metabolism including within the tumor microenvironment
4) Targeting carbohydrate metabolism including glycolysis, TCA cycle, or pentose phosphate pathway
5) Targeting ETC
6) Targeting amino acid metabolism including glutamine metabolism, cysteine metabolism.
7) Inducing metal dependent cell death pathways including ferroptosis, cuproptosis, pyroptosis in cancer cells
8) Targeting autophagy and mitophagy
9) Tumor stromal crosstalk and its effect on metabolic flux

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This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

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  • Case Report
  • Clinical Trial
  • Data Report
  • Editorial
  • General Commentary
  • Hypothesis and Theory
  • Methods
  • Mini Review

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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

  • Brief Research Report
  • Case Report
  • Clinical Trial
  • Data Report
  • Editorial
  • General Commentary
  • Hypothesis and Theory
  • Methods
  • Mini Review
  • Opinion
  • Original Research
  • Perspective
  • Review
  • Systematic Review
  • Technology and Code

Keywords: Metabolism, Signaling, TCA, Glycolysis, ROS, fatty acid oxidation, metal dependent cell death pathways, Autophagy, Mitophagy, Integrated stress response

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