Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, is increasingly understood as a malignancy shaped by profound changes in cellular metabolism. A comprehensive review published in
Genes & Diseases highlights how these metabolic alterations contribute to tumour growth, immune evasion and treatment resistance, while revealing potential opportunities for new therapeutic approaches.
A central feature of
ccRCC is disruption of the
VHL-HIF signalling axis. Loss or inactivation of the
VHL gene, which occurs in up to 90% of cases, can lead to persistent accumulation of
hypoxia-inducible factors (HIFs). This creates a pseudohypoxic state that reshapes tumour metabolism and supports processes including proliferation, angiogenesis, invasion and metastasis.
This metabolic rewiring extends across several interconnected pathways. ccRCC cells display altered
glucose metabolism, extensive
lipid accumulation, abnormal
amino acid metabolism and changes in
lactate metabolism and mitochondrial function. Together, these adaptations help cancer cells obtain energy and building materials while maintaining conditions that support survival. They can also contribute to an
immunosuppressive tumour microenvironment, potentially reducing the effectiveness of existing treatments.
Several metabolic components therefore represent potential therapeutic targets. These include glucose transporters such as
GLUT1 and
SGLT2, glycolytic enzymes including
HK2,
PFKFB3,
PKM2 and
PDK1, and regulators of lactate transport and production such as
LDHA and
MCTs. Lipid-related targets include
ACLY,
ACC,
FASN,
SCD1,
CD36 and
CPT1A, while altered glutamine, tryptophan and arginine metabolism provides additional avenues for intervention.
Some metabolism-targeting agents have already reached clinical evaluation, although progress varies considerably between targets. The therapeutic picture remains complex: tumour cells can compensate when one metabolic pathway is blocked, potentially limiting single-target approaches.
Future progress may therefore depend on
combination therapies,
multi-target inhibitors, improved biomarkers and approaches capable of accounting for metabolic differences within individual tumours. Integrating metabolic interventions with
immune checkpoint inhibitors and other established treatments could provide a route toward overcoming resistance and developing more personalized strategies for ccRCC.
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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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Reference
Jia-tao Yao, Peng-cheng Hu, Xiao-wei Li, Jia-cheng Xu, Ke-jie Wang, Sha-zhou Ye, Xiang-yu Meng, Hai-chao Chen, Yu Liang, Qi Ma, Research progress in metabolic reprogramming and targeting metabolic pathways for clear cell renal cell carcinoma, Genes & Diseases, Volume 13, Issue 6, 2026, 101991,
https://doi.org/10.1016/j.gendis.2025.101991
Funding
Ningbo Clinical Research Center for Urological Disease (China)
2019A21001
Ningbo Top Medical and Health Research Program (China)
2022020203
Zhejiang Engineering Research Center of Innovative technologies and diagnostic and therapeutic equipment for urinary system diseases; Zhejiang Provincial Medical and Health Science and Technology Program (China)
2025KY1317
Ningbo Natural Science Foundation (China)
2024J342