Review highlights how altered metabolism drives kidney cancer growth

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 tumor 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 tumor 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 tumor 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: tumor 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 tumors. 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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Compuscript Ltd

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