In oncology, returning to first principles matters: the cell is the unit of life and of medicine, and when a cell becomes malignant it changes how it feeds. Cancer cells hoard glucose, reroute amino acids, siphon lipids and improvise new fuel pathways when others are blocked. Clinical advances have targeted DNA, signaling and the immune system, but metabolism has been relatively neglected as a direct therapeutic focus.
A century ago Otto Warburg described how many cancer cells consume glucose and convert it to lactate even when oxygen is present. That observation faded as genetics dominated cancer research, but tumors are plastic and often evade therapy by rewiring their metabolism. Treating metabolism as a first-class target means moving beyond generic “cancer diets” and toward tumor-informed interventions tailored to a tumor’s biology, the treatment being given, and the patient’s physiology.
One clinical scenario illustrates the principle. A woman in her 50s with hormone receptor–positive, HER2‑negative breast cancer and a PIK3CA mutation receives a PI3K inhibitor with endocrine therapy. Initial benefit is followed by progression as drug-induced insulin and glucose rises create an alternate fuel route for the tumor. Pairing the drug with a dietary plan designed to blunt postprandial glucose and insulin spikes, timed to dosing and monitored with metabolic biomarkers, can narrow that escape route and deepen response. The effect depends on the combination—drug plus metabolism—not either alone.
Tumors compete with their microenvironment for nutrients and use different fuels in different organs. Some cancers depend on asparagine, others on serine and glycine; methionine restriction can alter one‑carbon metabolism and sensitize tumors to therapy. These are mechanistic insights, not folklore. Tumor-informed metabolism treats food as information: for a patient on a PI3K‑pathway inhibitor, the goal may be to flatten glucose and insulin peaks; for a colorectal cancer reliant on specific amino acids, it may be to limit those substrates during chemotherapy or radiation. For patients at risk of cachexia, the priority is preserving weight and muscle to maintain treatment intensity.
Clinical work is underway. At Faeth Therapeutics and in other efforts, investigators are pairing diets with PI3K/AKT/mTOR inhibitors in endometrial cancer and testing amino acid‑restricted regimens in rectal cancer, scripting nutritional plans around drug mechanisms and treatment windows. The hope is not to advance a single company but to establish a template for rigorous nutrition–drug combinations that can be tested in randomized trials and treated as prespecified protocol elements rather than unmeasured background.
The field remains nascent. Preclinical and early clinical signals are encouraging when diets are matched to drug mechanisms, and disappointing when they are generic, prolonged, or misaligned. Many patients already face diabetes, weight loss or weakness during treatment, and poorly designed dietary interventions can do harm. Tumor-informed metabolism should function as a targeted adjuvant—time‑limited, measurable and delivered with the same rigor and safeguards as a medication.
Making this standard care will require prospective, controlled studies with objective endpoints—response, survival, preserved dose intensity and reduced toxicity—and clinical structures to implement findings. That includes multimodal regimens that block signaling without undermining immune responses; precision nutrition that specifies macronutrient and micronutrient targets, timing and contraindications; and computational models of metabolism to predict fluxes, anticipate resistance and prioritize combinations before clinical testing.
Equity must be central. If metabolic therapies become precision tools, they must be accessible, covered by payers and adaptable to diverse cultural and economic settings, not confined to concierge care.
If the cell is the unit of life, metabolism is a primary expression of its state. Oncology has broadened what counts as therapy before—surgery, chemotherapy, immunotherapy—and it can do so again by braiding pharmacology with targeted metabolic interventions. Sequencing, drugs and patient care will remain essential, but integrating precise nutrition into treatment plans offers a concrete way to strengthen responses and extend benefit.
Siddhartha Mukherjee, M.D., D.Phil., is an oncologist, researcher and author. He is associate professor of medicine at Columbia University, co‑founder of several biotechnology ventures including Faeth Therapeutics and Manas AI, and author of The Emperor of All Maladies, now available in a new edition with four new chapters.
Leave a Reply