Food, Dietary Supplement, and Gut Microbiome Interactions in Oral Anticancer Therapy: Mechanisms, Clinical Consequences, and Management

BACKGROUND: The shift toward oral targeted therapies and immune checkpoint inhibitors (ICIs) in oncology has introduced pharmacokinetic variability driven by food-drug interactions (FDIs), which can cause therapeutic failure or increased toxicity. AREAS OF UNCERTAINTY: FDI effects depend on drug composition and food-intake timing. Evidence for traditional antineoplastic drugs is well documented, but data on newer targeted therapies and on diet-mediated or microbiome-mediated modulation of ICI efficacy remain inconsistent-dietary fiber and probiotic supplementation, for example, appear associated with divergent clinical outcomes. The role of high-dose antioxidant supplementation during cytotoxic therapy also requires further study. DATA SOURCES: A structured search of Web of Science, PubMed, and Embase (through July 2026) informed this narrative review of pharmacokinetic mechanisms, clinical outcomes, and management strategies for the concomitant use of food, dietary supplements, and antineoplastic drugs. RESULTS: Food can alter oral antineoplastic drug bioavailability through changes in gastric pH, cytochrome P450 (CYP) modulation, and efflux-transporter inhibition (eg, P-glycoprotein). High-fat meals increase exposure to tyrosine kinase inhibitors (TKIs) such as lapatinib and abiraterone, while newer agents (sotorasib and lorlatinib) show different food-interaction profiles. ICI efficacy correlates with gut microbiome composition, modulated by dietary fiber and short-chain fatty acid production. High-dose antioxidant supplementation during cytotoxic therapy may compromise treatment outcomes. CONCLUSION: Food-drug interactions are an increasingly important clinical concern in modern oncology. Pharmacokinetic interactions mediated by gastric pH, CYP3A4, and P-glycoprotein transport are well supported by clinical data and already inform drug labeling, whereas diet-microbiome-immunotherapy associations remain less mature and should be regarded as hypothesis generating. Structured, multidisciplinary management-periodic regimen review, patient education, decision algorithms, and therapeutic drug monitoring-can mitigate established risks, while prospective studies are still needed before diet-based and microbiome-based interventions can be considered clinically actionable.