Science AI Journal
Biochemistry, Genetics and Molecular Biology · Research topic

Open research questions in Cancer, Hypoxia, and Metabolism

65 unresolved questions extracted from the limitations and future-work sections of 331 Cancer, Hypoxia, and Metabolism papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The mesenchymal homeobox transcription factor MEOX2 is recognized for its roles in development and homeostasis, but the full landscape of its complex and often contradictory functions in human diseases, along with its potential unifying regulatory logic, remains to be systematically elucidated.

    MEOX2: a homeobox transcription factor with multifaceted biological functions and broad disease associations · 2026 · DOI

  • Lysyl oxidase (LOX), an extracellular matrix remodeler widely implicated in tumor progression; however, whether LOX regulates energy metabolism and mitochondrial homeostasis in cancer cells remains poorly understood.

    Abstract B081: Lysyl oxidase inhibitor LXG6403 creates ferroptosis vulnerability in triple-negative breast cancer · 2026 · DOI

  • Abstract Although receptor tyrosine kinase inhibitors (sorafenib and lenvatinib) have been applied as a first-line targeted therapy for advanced unresectable hepatocellular carcinoma (HCC) for decades, their clinical efficacy is limited and the underlying mechanism remains unclear.

    AARS1-catalyzed H4K12 lactylation promotes HCC resistance to targeted therapy by activating RAPGEF3-RAP1 signaling · 2026 · DOI

  • In support of this, glycogen metabolism has previously been implicated in cancer biology across multiple tumor types, however the available data remain scarce, hetero- geneous, and derived from studies that do not distinguish metastatic status (Curtis et al, 2019; Liu et al, 2021; Altemus et al, 2019).

    Metabolic buffering restricts phenotype switching in melanoma · 2026 · DOI

  • Despite its structural similarity to other CAT family members, convincing evidence for its membrane localization, cationic amino acid transport activity, and cancer‐associated functions is still lacking.

    The Pathological Roles of Cationic Amino Acid Transporters ( <scp>CATs</scp> ) in Cancer · 2026 · DOI

  • AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, but its role in cachexia and its therapeutic potential remains incompletely defined.

    Combined AMPK activation and ghrelin ameliorate cancer cachexia through complementary effects on energy homeostasis, inflammation, and wasting · 2026 · DOI

  • The fact that PKM2 knockdown or TEPP-46 treatment attenuated HIF-1α protein levels and its downstream signaling without affecting HIF1A mRNA transcription suggests a post- translational regulatory mechanism, potentially involving stabilization or enhanced transactivation, which warrants further investigation.

    Nuclear translocation of pyruvate kinase M2 drives high glucose-induced angiogenesis in retinal endothelial cells via the HIF-1α axis · 2026 · DOI

  • However, the determinants of BETi sensitivity and the underlying mechanisms of response remain poorly understood, particularly in the context of metabolic reprogramming.

    BET inhibition unmasks a targetable glycolytic dependency through a HIF1α stabilization and driven transcriptional program in a defined subset of triple-negative breast Cancer · 2026 · DOI

  • Monocarboxylate transporter 4 (MCT4) is a key lactate exporter often overexpressed in cancers, yet its precise role in HCC pathogenesis and immune modulation remains incompletely defined.

    MCT4 drives HCC progression by activating MMPs and polarizing M2 macrophages · 2026 · DOI

  • The ultimate goal of this section is to utilize AI tools to identify relationships between myeloid subsets and immunometabolic states. In this context, two representative studies—using neural network-based flux estimation (scFEA) and genome-scale metabolic modeling (COMPASS)—guide the way for AI to resolve immunometabolic questions. Specifically, Wang et al. utilized scFEA to delineate the metabolic-functional landscape of myeloid subsets within the hypoxic TME of colorectal and lung cancers. By applying this neural network-based framework to scRNA-seq data, the authors inferred that lactate was the most notably accumulated metabolite within myeloid compartments, role of reinforcing the central the lactate axis in myeloid reprogramming. Furthermore, scFEA identified that APOE+CTSZ+ TAMs, a subset characterized by anti-inflammatory and M2-like signatures, exhibit uniquely high glutamate-to-glutamine flux and glutamate transport135. The utility of AI in resolving immune-metabolic complexity is further demonstrated by the COMPASS framework, which integrates single-cell transcriptomes with genome-scale metabolic models that includes reaction stoichiometry, biochemical constraints such as reaction irreversibility, nutrient availability and gene–enzyme–reaction associations. COMPASS was utilized on scRNA-seq profiles to clarify the metabolic divergence between pathogenic Th17 cells and nonpathogenic Th17 cells. Following an AI-driven finding of systemic metabolic differences, the authors validated the inferred metabolic states of individual cells through metabolic assays. This systematic pipeline led to the identification of the polyamine pathway as a master regulator of Th17 function. in vivo perturbations of the polyamine pathway Importantly, altered the phenotype of encephalitogenic T cells and attenuated tissue inflammation in central nervous system autoimmunity26. These case studies illustrate how AI-driven frameworks transcend the inherent limitations of transcriptomics by inferring metabolic flux in the absence of matched metabolomics. By establishing a systematic pipeline, transitioning from AI-driven inference to mechanistic identification and functional validation, these tools provide a strategic roadmap for decoding how the immunometabolic states dictate the heterogeneous fates of myeloid cells within the complex TME. Highlight emerging AI frameworks for in silico drug repurposing targeting MCTs or NAMPT A highly impactful application of these AI frameworks is the in silico repurposing of existing drugs against new metabolic targets. This strategy is particularly promising for tumor myeloid cells, which are often ‘addicted’ to specific metabolic pathways. Highdemand targets include lactate metabolism (for example, LDH-A and MCT) and the NAD+ salvage pathway (for example, NAMPT).

    Metabolic reprogramming of myeloid cells in cancer: from lactate–NAMPT axis to AI-guided therapeutics · 2026 · DOI

  • Yet, how CDK4/6 inhibition intersects with estrogen-regulated glycolytic control to rewire glucose utilization in ER⁺ breast cancer has not been explored.

    Targeting PFKFB3 to enhance CDK4/6 inhibitor response in ER+ breast cancer · 2026 · DOI

  • Future studies should focus on the development of specific tools to detect, modulate and visualize lactylation dynamics in vivo. The full repertoire of lactylated proteins, their site‑specific regulatory mechanisms, and their functional implications in different cancer types and stages remain to be fully elucidated. Additionally, there is a lack of standardized models to evaluate the synergistic effects of combining lactate metabo‑ lism inhibitors with epigenetic drugs.

    Understanding the epigenetic regulation of lactylation and aberrant lactate metabolism in cancer: From mechanisms to therapeutic strategies (Review) · 2026 · DOI

  • Second, the specific interaction sites among molecules in the pathway, as well as the downstream regulatory targets through which RUNX1 antagonizes the tumor−suppressive effect of CBFb−MYH11, have not been fully elucidated. In addition, the crosstalk between this core pathway and other signaling pathways in the hypoxic tumor microenvironment has not been systematically investigated.

    Hypoxia induced DNMT3B and SHP2 signaling promoted HCC via suppressing P53 and MYH11 protein expression · 2026 · DOI

  • However, this framework overlooks an important dimension of CAF biology, metabolic heterogeneity, which remains insufficiently characterized and is not incorporated into current classification systems.

    Glycolytic cancer-associated fibroblasts orchestrate metabolic remodeling in the tumor microenvironment · 2026 · DOI

  • Osteosarcoma (OS) exhibits profound metabolic reprogramming, yet the specific cellular subpopulations and regulatory networks governing glycolysis within the tumor microenvironment remain elusive.

    Single-cell transcriptomics reveals glycolytic heterogeneity and identifies STC2 as a key regulator of metabolic reprogramming in osteosarcoma · 2026 · DOI

  • The next phase of cancer immunometabolism research will require greater spatial, temporal, and cellular resolution. Tumors are metabolically heterogeneous ecosystems, and nutrient gradients vary across regions, disease stages, and therapeutic contexts. spatial Integrating metabolomics, transcriptomics, single-cell profiling, and functional immune analyses will be essential to map how metabolic circuits evolve during progression and treatment. Therapeutically, the challenge is no longer simply to inhibit tumor metabolism but to recalibrate metabolic ecosystems. Because immune cells share many metabolic dependencies with tumor cells, indiscriminate metabolic blockade risks impairing anti-tumor immunity. Rational combination strategies (pairing tumordirected metabolic inhibitors with ICB, co-stimulatory agonists, or adoptive cell therapies) offer a more nuanced approach. In parallel, therapeutic lymphocytes may enhance their resilience within nutrient- and oxygen-restricted environments. conditioning of vivo metabolic ex A deeper understanding of metabolic plasticity will also be crucial. Many suppressive immune populations thrive precisely because they exploit alternative fuel sources. Identifying contextspecific metabolic vulnerabilities, rather than broadly targeting entire pathways, may allow selective disruption of tumorpromoting circuits while preserving or enhancing effector function. Ultimately, metabolic pathway rewiring should be viewed not merely as a hallmark of cancer but as a strategic battlefield. By learning how to manipulate the rules of metabolic engagement, future therapies may transform the tumor–immune tug-of-war into a coordinated and sustained anti-tumor response. Frontiers in Cell and Developmental Biology 29 frontiersin.org Foglia et al.

    Tumor–immune metabolic tug-of-war: from immune escape to targeting metabolic rewiring in cancer therapy · 2026 · DOI

  • Research on lactate metabolism and lactate-derived lactylation, as core drivers of cancer initiation and progression, is gradually changing our traditional perception of lactate as a “metabolic 28 Lactate metabolism and lactylation in cancer: from pathogenesis to... Fang et al. waste product.” This review systematically examines the basic mechanisms of lactate metabolism, its abnormal manifestations in tumor cells, and the multiple roles of lactate in the TME. From the perspective of tumor initiation and progression, we reviewed the critical roles of lactate and lactylation modifications in transcriptional regulation, protein function modulation, immune evasion, and treatment resistance. The present review highlighted the role of lactate as an important mediator of signal transduction and epigenetic regulation, beyond its conventional function as an intermediate product of cellular metabolism. Mechanistically, tumor cells reprogram their metabolism to increase glycolysis, even under aerobic conditions (i.e., the Warburg effect), significantly increasing lactate production. Subsequently, glutamine metabolism becomes an important source of lactate, supporting the energy and biosynthetic precursor demands of rapid tumor proliferation while promoting immune suppression, angiogenesis, and metastasis by acidifying the TME. Additionally, the lactate shuttle mechanism facilitates metabolic symbiosis between different regions of tumor cells. Lactylation, a novel form of posttranslational protein modification, expands the connection between metabolic products and epigenetic regulation. The “writers” (such as p300, GCN5, and KAT8), “erasers” (such as HDACs and the SIRT family), and “readers” (such as Brg1 and DPF2) of lactylation constitute a highly dynamic regulatory system. These modifications are present on histones, regulating the open state and transcriptional activity of key genes. They also widely affect nonhistone proteins, influencing biological the cell cycle, and drug processes, resistance. The differences such as L-lactylation and D-lactylation, and their source pathways (enzymatic or nonenzymatic) also provide new insights into tumor molecular heterogeneity and therapeutic target development. in lactylation isomers, including DNA repair, Notably, lactate and lactylation exhibit significant dynamics and duality across different stages of cancer. During tumor initiation, lactate accelerates carcinogenesis by inducing DNA mutations, impairing tumor suppressor gene function (such as p53 lactylation), and remodeling the immune microenvironment. During it supports malignant clone tumor expansion and invasion, selection and expansion by acidifying the microenvironment and driving immune tolerance. Moreover, during cancer treatment, lactylation confers drug resistance by enhancing DNA repair and inhibiting immune responses.

    Lactate metabolism and lactylation in cancer: from pathogenesis to therapeutic advances · 2026 · DOI

  • While there is ample evidence showing that various glycolytic enzymes are active in multiple pathways apart from glycolysis, their regulatory functions in an AML-specific context are not yet understood.

    Glycolysis and glycolytic enzymes in acute myeloid leukemia: Warburg and beyond · 2026 · DOI

  • The study validated the combination strategy in only two NSCLC cell lines (H1975 with EGFR L858R/T790M, and A549); efficacy and synergistic effects must be evaluated across additional EGFR-mutant models (exon 19 deletions, exon 20 insertions, G719X mutations) and in cells with de novo or acquired erlotinib resistance mechanisms independent of HIF-1α activation.

    HIF-1α siRNA Enhances the Efficacy of Erlotinib in Non-small Cell Lung Cancer: A Novel Strategy to Reverse Hypoxia-Induced Drug Resistance · 2026 · DOI

  • The mechanism by which HIF-1α knockdown resensitizes EGFR L858R/T790M double-mutant cells to erlotinib through metabolic reprogramming requires investigation of whether resistance reversal depends primarily on glycolytic inhibition (GLUT1/PDK1), angiogenesis suppression (VEGFA/CA9), or extracellular matrix remodeling (MMP2/MMP9), and whether these pathways are independent or hierarchically regulated.

    HIF-1α siRNA Enhances the Efficacy of Erlotinib in Non-small Cell Lung Cancer: A Novel Strategy to Reverse Hypoxia-Induced Drug Resistance · 2026 · DOI

  • The study tested HIF-1α siRNA delivery only in standard cell culture conditions; optimal delivery methods (nanoparticles, viral vectors, lipid formulations) for in vivo HIF-1α siRNA administration in NSCLC models and the resulting pharmacodynamic effects on HIF-1α target genes (GLUT1, PDK1, CA9, MMP2) have not been characterized.

    HIF-1α siRNA Enhances the Efficacy of Erlotinib in Non-small Cell Lung Cancer: A Novel Strategy to Reverse Hypoxia-Induced Drug Resistance · 2026 · DOI

  • Patient stratification strategies and biomarkers to identify NSCLC patients most likely to benefit from HIF-1α siRNA combined with erlotinib therapy remain undefined; prospective clinical studies should evaluate HIF-1α expression levels, hypoxia signatures, and EGFR mutation status as predictive markers for treatment response.

    HIF-1α siRNA Enhances the Efficacy of Erlotinib in Non-small Cell Lung Cancer: A Novel Strategy to Reverse Hypoxia-Induced Drug Resistance · 2026 · DOI

  • The study demonstrates EGFR signaling regulates HIF-1α stability through PI3K/AKT and MEK/ERK pathways, but the upstream regulatory network involving PI3K, mTOR, and MAPK exhibits highly interconnected crosstalk with potential feedback loops that require deeper mechanistic dissection to understand context-dependent regulation in different EGFR-mutant backgrounds (e.g., L858R/T790M versus other EGFR mutations).

    HIF-1α siRNA Enhances the Efficacy of Erlotinib in Non-small Cell Lung Cancer: A Novel Strategy to Reverse Hypoxia-Induced Drug Resistance · 2026 · DOI

  • The paper does not investigate whether other histone lactylation sites beyond H3K18la contribute to the lactate-driven immune resistance phenotype, or whether H3K18la regulates other KIF20A-independent pathways relevant to HCC progression. A comprehensive ChIP-seq and RNA-seq analysis across multiple lactate concentrations and time points would clarify the scope of H3K18la-mediated transcriptional reprogramming.

    Lactate drives immune resistance via a pharmaceutically reversible H3K18la-KIF20A-c-Myc-PD-L1 axis in hepatocellular carcinoma · 2026 · DOI

  • The study identifies H3K18la as a direct target of lactate-driven histone lactylation but does not comprehensively characterize which histone acetyltransferases or lactate sensor proteins specifically catalyze or recognize H3K18la modifications in HCC cells. The identity and regulation of the enzymatic machinery linking lactate metabolism to H3K18la deposition requires systematic investigation.

    Lactate drives immune resistance via a pharmaceutically reversible H3K18la-KIF20A-c-Myc-PD-L1 axis in hepatocellular carcinoma · 2026 · DOI

Most-cited papers in Cancer, Hypoxia, and Metabolism

Most recent work

Find a gap in your own Cancer, Hypoxia, and Metabolism sub-topic

This page shows what the Cancer, Hypoxia, and Metabolism literature already flags as unresolved. To narrow it to your specific question, run the guided finder — it searches the gap library on demand and checks candidates against 250M+ OpenAlex works.

Open the Research Gap Finder →

Related topics in Biochemistry, Genetics and Molecular Biology

Gut microbiota and health
289 open questions
Single-cell and spatial transcriptomics
185 open questions
dental development and anomalies
121 open questions
Mitochondrial Function and Pathology
110 open questions
Genetic Associations and Epidemiology
106 open questions
Human-Animal Interaction Studies
105 open questions
Genomics and Chromatin Dynamics
97 open questions
Inflammatory Bowel Disease
91 open questions
65 open questions have been extracted from the limitations and future-work passages of 331 Cancer, Hypoxia, and Metabolism papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

Tools for your next paper

Gaps & Literature SearchFind open questions in any field — 120,000+ open gaps mined from our own library.Pre-CheckIs your paper ready? A Tier 1–5 acceptance probability in seconds.Journal FinderA ranked shortlist of target journals from a 17,500-venue index.Duplicate Publication CheckerCheck prior-publication & salami-slicing risk across 8 sources.Citation GeneratorFreeA DOI or title → APA, MLA, Vancouver, Chicago, BibTeX, RIS. No signup.Graphical Abstract MakerFreeTurn your findings into a colorblind-safe graphical abstract.

Compare the category — Honest roundups of the AI research tools, ours listed alongside the alternatives.

Command palette

Jump anywhere, run any action.