Open research questions in Cancer, Hypoxia, and Metabolism

What the literature leaves open

• The role of fructose in ccRCC is underexplored despite its potential impact on tumor growth and metabolism. The mechanisms underlying the paradoxical fructose metabolism signature in ccRCC are not well understood. The effect of fructose on ccRCC cell proliferation and mitochondrial function is not fully elucidated.

  Fructose induces PERK-dependent ER stress and mitochondrial dysfunction via nucleotide depletion in clear cell renal cell carcinoma · 2026 · DOI

• Future efforts should prioritize translating mechanistic understandings into precision therapies that target cancer cells and modulate their supportive adipose niches. The complexity and heterogeneity of the adipose–tumor interface necessitate integrated, multidisciplinary approaches combining molecular insights with clinical strategies.

  Cancer-associated adipocytes: metabolic reprogramming, crosstalk and therapeutic implications in tumor progression · 2026 · DOI

• Elucidating how lactylation influences the functional traits of metabolic enzymes, - Exploring whether targeting lactylation of metabolic enzymes could emerge as a therapeutic avenue

  When metabolic enzymes meet lactylation: a bidirectional dialogue in health and disease · 2026 · DOI

• The complexity of the lactate-lactylation axis and its regulation. The need for further clinical investigation to determine the role of lactylation-associated pathways in predicting immunotherapy response. The challenge of translating experimental findings into clinical applications.

  The Lactate–Lactylation Axis as a Metabolic–Epigenetic Framework for Therapeutic Adaptation in Esophageal Squamous Cell Carcinoma · 2026 · DOI

• the role of lactylation-associated pathways in predicting immunotherapy response requires further clinical investigation, - most supporting evidence comes from experimental models, animal studies, or investigations in other malignancies, - clinical validation in ESCC remains scarce, - the study did not include chemotherapy-specific response assessments

  The Lactate–Lactylation Axis as a Metabolic–Epigenetic Framework for Therapeutic Adaptation in Esophageal Squamous Cell Carcinoma · 2026 · DOI

• The lack of direct targeting evidence for PFKP in clinical settings. The need for further research on PFKP's non-canonical functions and its role in immune remodeling. The requirement for more studies on the translational potential of PFKP as a diagnostic and prognostic marker.

  PFKP in malignant tumors: bridging metabolic reprogramming, post-translational modifications, and the immunosuppressive microenvironment · 2026 · DOI

• exploring novel therapeutic strategies for DLBCL, - investigating the effects of ouabain on other types of cancer, - further studies are needed to fully understand the mechanism of action of ouabain

  Integrative proteomic and metabolomic analysis reveals that ouabain inhibits DLBCL proliferation by reprogramming arginine-driven metabolic networks · 2026 · DOI

• The mechanism of action of ouabain in inhibiting DLBCL proliferation is not yet fully understood. Current therapies for DLBCL have limitations, with approximately 30%-40% of patients developing relapsed or refractory disease.

  Integrative proteomic and metabolomic analysis reveals that ouabain inhibits DLBCL proliferation by reprogramming arginine-driven metabolic networks · 2026 · DOI

• The development of effective therapeutic strategies to target mitochondrial vulnerabilities and enhance immunotherapy responses. The need to understand the complex relationship between mitochondrial pathways and tumor immune escape. The challenge of overcoming resistance to immunotherapy in colorectal cancer.

  Mitochondrial dysfunction as a metabolic checkpoint of immunotherapy response in colorectal cancer · 2026 · DOI

• investigation of combination strategies targeting mitochondrial metabolism, - studying the effects of chronic mitochondrial dysfunction on immune escape, - exploring the potential of mitochondria-targeted strategies for pMMR/MSS CRC and dMMR/MSI-H tumors with primary or acquired ICI resistance

  Mitochondrial dysfunction as a metabolic checkpoint of immunotherapy response in colorectal cancer · 2026 · DOI

• Investigate the effects of acidic conditions on other types of cancer cells, - Examine the role of other signaling pathways in pancreatic cancer cell survival under acidic conditions, - Conduct in vivo studies to validate the findings

  Acidic microenvironment promotes pancreatic cancer cell survival via Akt phosphorylation-mediated suppression of apoptosis · 2026 · DOI

• Investigating cell-intrinsic solutions to engineer infused cells for acidic resilience, - Exploring co-administration of TME-normalizing agents to improve resilience, - Developing pharmacological tools to target nodes of the acidity axis

  The acidic tumor microenvironment in hepatocellular carcinoma: a barrier to adoptive cellular immunotherapy · 2026 · DOI

• epigenetic regulation, - functional characterization of interacting partners, - combination strategies with immunotherapy

  PFKP in malignant tumors: bridging metabolic reprogramming, post-translational modifications, and the immunosuppressive microenvironment · 2026 · DOI

• The specific implications of acidosis for the design and delivery of cell-based therapies remain scattered and unsynthesized. The incomplete dissociation of acidity- versus lactate-mediated effects is an unresolved issue. The gap between preclinical pH modulation and clinical translation is an area that requires further research.

  The acidic tumor microenvironment in hepatocellular carcinoma: a barrier to adoptive cellular immunotherapy · 2026 · DOI

• Although metabolic adaptations and autophagy support PGCC formation and survival, the mechanisms underlying these processes and their contribution to tumor relapse remain poorly understood.

  The Sleeping Giant: Metabolism and Autophagy in the Generation and Survival of Dormant Polyploid Giant Cancer Cells · 2026 · DOI

• ABSTRACT A major limitation in preventing cancer relapse is our incomplete understanding of therapy resistance and tumor dormancy, including the role of therapy‐induced polyploidy in generating rapidly proliferating progeny that repopulate the tumor.

  The Sleeping Giant: Metabolism and Autophagy in the Generation and Survival of Dormant Polyploid Giant Cancer Cells · 2026 · DOI

• Hypoxia-inducible factor α (HIFα) governs glycolysis but does not directly regulate glutamine metabolism; instead, the factor responsible for orchestrating glutamine metabolism and mitochondrial adaptations to hypoxia remains elusive.

  ZNF395 Is a Hypoxia-Responsive Regulator of Mitochondrial Glutaminolysis in Clear Cell Renal Cell Carcinoma · 2026 · DOI

• Collectively, these findings may be consistent with differential changes in proliferation-associated and survival-associated signaling under extracellular acidosis, although the functional relationships among these changes remain uncertain.

  Acidic microenvironment promotes pancreatic cancer cell survival via Akt phosphorylation-mediated suppression of apoptosis · 2026 · DOI

• Alternative splicing (AS) is increasingly recognized as a key regulator of cancer metabolism, yet its specific impact on TCA cycle enzymes remains unclear.

  Alternatively Spliced Citrate Synthase Supports Colorectal Cancer · 2025 · DOI

• The dynamic regulation and differences among these three modifications in response to hypoxia remain poorly understood.

  Dynamic investigation of hypoxia-induced L-lactylation · 2025 · DOI

• However, the specific regulatory mechanisms and downstream target proteins remain unclear.

  High Sugar Induced RCC2 Lactylation Drives Breast Cancer Tumorigenicity Through Upregulating MAD2L1 · 2025 · DOI

• However, effective treatment strategies for cisplatin resistance have not been well established.

  SRC enhanced cisplatin resistance in bladder cancer by reprogramming glycolysis and pentose phosphate pathway · 2025 · DOI

• While CAFs are known to influence tumor metabolism, the specific mechanisms underlying their role in metabolic adaptation remain unclear.

  CAF-derived GLUT1 and its role in modulating ovarian cancer progression: a multi-dimensional analysis of the tumor microenvironment · 2025 · DOI

• However, the specific impact of PDHB on hepatocellular carcinoma (HCC) metabolic reprogramming and its role in tumor progression remain to be elucidated.

  Isoacteoside alleviates hepatocellular carcinoma progression by inhibiting PDHB-mediated reprogramming of glucose metabolism · 2025 · DOI

• However, when the fatty acid degradation pathway is activated, lipid accumulation still occurs, suggesting the presence of unknown pathways and mechanisms that remain to be elucidated.

  Arginine Metabolism Reprogramming in Perfluorooctanoic Acid (PFOA)-Induced Liver Injury · 2025 · DOI

Most-cited papers in Cancer, Hypoxia, and Metabolism

• Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation · Science · 2009 · 14,120 citations
• Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O 2 -Regulated Prolyl Hydroxylation · Science · 2001 · 4,832 citations
• HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing · Science · 2001 · 4,156 citations
• Cancer-associated IDH1 mutations produce 2-hydroxyglutarate · Nature · 2009 · 3,505 citations
• A pathology atlas of the human cancer transcriptome · Science · 2017 · 2,988 citations
• The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth · Nature · 2008 · 2,391 citations
• Metabolic reprogramming and cancer progression · Science · 2020 · 2,363 citations
• Hypoxia and Inflammation · New England Journal of Medicine · 2011 · 1,862 citations
• The role of ROS in tumour development and progression · Nature reviews. Cancer · 2022 · 1,518 citations
• The hallmarks of cancer metabolism: Still emerging · Cell Metabolism · 2022 · 1,319 citations

Most recent work

• Targeting Lactate and Lactylation in Cancer Metabolism and Immunotherapy · Advanced Science · 2026
• β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer · Cell · 2026
• Lactylation in cancer: mechanistic insights, tumor microenvironment, and therapeutic horizons · Frontiers in Immunology · 2026
• The tumor microenvironment: adding pieces to the puzzle · Frontiers in Immunology · 2026
• Immune cell metabolic reprogramming in hepatocellular carcinoma: mechanisms, tumor microenvironment, and future immunotherapeutic directions · Frontiers in Immunology · 2026
• HIF-1α as a Central Regulator of Monocyte Responses to Hypoxia · Biology · 2026
• Hypoxia-inducible factors link inflammation and lipid metabolism in atherosclerotic macrophages · Frontiers in Cardiovascular Medicine · 2026
• Metabolic reprogramming and immunosenescence: a new sight for glioma therapy · Frontiers in Cell and Developmental Biology · 2026
• Metabolic crosstalk between oral microbiota and the host in OSCC: emerging roles of microbial metabolites in tumor initiation and progression · Frontiers in Cellular and Infection Microbiology · 2026
• Lysine lactylation regulates ATF4-mediated stress responses under glucose starvation in canine hemangiosarcoma · Frontiers in Veterinary Science · 2026

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