Nutritional approaches in combating therapeutic resistance and enhancing treatment efficacy in cancer: the impact of ketogenic diets

Sep 24, 2026

Cancer remains a major global health challenge, with therapeutic resistance significantly limiting treatment success. Traditional approaches, including surgery, chemotherapy, and radiotherapy, often face barriers such as metastasis and adverse effects on healthy tissues. Drawing on the Warburg effect, this review evaluates ketogenic diets (KD) as high-fat, low-carbohydrate interventions that may selectively impair malignant cells while preserving normal function, potentially targeting PI3K/Akt/mTOR, IGF-1 signaling, and drug sensitivity, though large RCT evidence is still limited and adherence challenges remain.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages21

Reading Time53 min

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Wang et al. Nutrition & Metabolism (2026) 23:6 Nutrition & Metabolism [https://doi.org/10.1186/s12986-025-01055-3](https://doi.org/10.1186/s12986-025-01055-3) REVIEW Open Access Nutritional approaches in combating therapeutic resistance and enhancing treatment efficacy in cancer: the impact of ketogenic diets Lei Wang 1, Pezhman Shafiei Asheghabadi2,3, Saba Mashhadikhan2, Sevda Nasirzade2, Yeganeh Ettehad2, Sepideh Gholamrezaie2, Fatemeh Jafari2, Maryam Rahmani2,4, Shaghayegh Mehdizadeh2,4, Neda Zali3, Najma Farahani2, Russel J. Reiter5, Maliheh Entezari2,6*, Mina Alimohammadi7*, Afshin Taheriazam2,8*, Payman Rahimzadeh9*, Kiavash Hushmandi 10 and Mehrdad Hashemi2,6* Abstract Cancer remains a major global health challenge, with therapeutic resistance significantly limiting treatment success. Traditional approaches, including surgery, chemotherapy, and radiotherapy, often encounter barriers such as metastasis and adverse effects on healthy tissues. The Warburg effect, which describes cancer cells’ reliance on glucose fermentation despite oxygen availability, has prompted investigations into alternative metabolic interventions. The ketogenic diet (KD), characterized by high fat intake and low carbohydrate intake, induces a metabolic shift that may selectively disadvantage malignant cells while preserving normal tissue function. While emerging evidence, including preclinical studies, early-phase trials, and limited clinical series, suggests that KD may help overcome treatment resistance by suppressing the PI3K/Akt/mTOR pathway, reducing insulin-like growth factor-1 (IGF-1) signaling, and enhancing cancer cell susceptibility to chemotherapy and targeted therapies, robust data from large, randomized controlled trials (RCTs) remain sparse. Most current findings derive primarily from animal models and small pilot studies, with definitive efficacy and safety in broad patient populations yet to be established. Preclinical and preliminary clinical studies indicate KD’s potential in modulating epigenetic markers, reducing inflammation, and improving patient metabolic health. However, patient adherence remains challenging and standardized protocols are still under development. This review explores the molecular mechanisms underlying *Correspondence: Maliheh Entezari [mentezari@iautmu.ac.ir](mentezari@iautmu.ac.ir) Mina Alimohammadi[mina.alimohammadi11@gmail.com](mina.alimohammadi11@gmail.com)[ ](mina.alimohammadi11@gmail.com)Afshin Taheriazam[a.taheriazam@iautmu.ac.ir](a.taheriazam@iautmu.ac.ir)[ ](a.taheriazam@iautmu.ac.ir)Payman Rahimzadeh [P.rahimzadeh76@gmail.com](P.rahimzadeh76@gmail.com)[ ](P.rahimzadeh76@gmail.com)Mehrdad Hashemi [mhashemi@iautmu.ac.ir](mhashemi@iautmu.ac.ir) Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/l](http://creativecommons.org/l)icenses/by/4.0/. KD’s anticancer effects, its role in mitigating drug resistance, and current translational insights, with emphasis on the nascent stage of high-quality clinical trial evidence and areas for future research. Key points • Traditional treatments often harm healthy tissue and may

FAQs

Why does therapeutic resistance reduce the effectiveness of cancer treatments?

Therapeutic resistance limits treatment success by allowing cancer cells to survive or adapt despite standard therapies. This contributes to barriers such as disease progression and treatment failure.

What is the Warburg effect and how is it connected to ketogenic diets?

The Warburg effect describes cancer cells’ reliance on glucose fermentation for energy even when oxygen is available. This rationale motivates metabolic interventions like ketogenic diets to disrupt cancer cell fuel usage.

What evidence supports ketogenic diets for overcoming drug resistance, and what limits the current conclusions?

Preclinical studies, early-phase trials, and limited clinical series suggest ketogenic diets may reduce signaling pathways and enhance susceptibility to therapies. However, robust large randomized controlled trial data and standardized, widely applicable protocols are still sparse, and patient adherence remains challenging.

Sep 24, 2026

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