Nature Communications | Feasibility Study of a Very Low-Carbohydrate Ketogenic Diet in Endometrial Cancer Patients

This study provides direct clinical evidence for metabolic intervention in endometrial cancer patients with obesity, indicating that a very low-carbohydrate diet is not only safe and feasible but also significantly improves insulin resistance and enhances CD8+ T cell infiltration in the tumor microenvironment, offering new directions for designing subsequent clinical strategies combining immunotherapy.

 

Literature Overview

The article titled 'Very low-carbohydrate ketogenic diet in treatment-naïve women with endometrial cancer and overweight: a randomized feasibility study,' published in Nature Communications, systematically investigates the feasibility, safety, and impact of a very low-carbohydrate ketogenic diet (VLCD) on systemic metabolism and tumor biology in treatment-naïve female patients with endometrial cancer and overweight or obesity. Using a multicenter, prospective, randomized controlled design, the study implemented short-term dietary intervention during the preoperative window and comprehensively evaluated the effects through nutritional counseling, metabolic monitoring, and tumor tissue analysis. The results show that VLCD is highly feasible and well tolerated in this population, significantly reducing insulin levels, and unexpectedly enhancing CD8+ T cell infiltration at the tumor margin. These findings provide important evidence for the application of metabolic reprogramming in the treatment of gynecological cancers.

Background Knowledge

Endometrial cancer is the most common gynecological malignancy worldwide, and its incidence is closely associated with obesity, with approximately 50% of cases linked to overweight or obesity. Obesity promotes the development and progression of endometrial cancer through mechanisms such as insulin resistance, hyperinsulinemia, chronic inflammation, and sex hormone imbalance. Among these, aberrant activation of the PI3K/AKT/mTOR signaling pathway is the most common molecular event in endometrial cancer, with over 90% of tumors harboring genetic mutations in this pathway, such as PIK3CA activation or PTEN loss. Elevated insulin levels can further activate PI3K signaling, creating a pro-cancer positive feedback loop. Although substantial evidence supports a link between high dietary glycemic load and endometrial cancer risk, no study has systematically assessed the impact of low-carbohydrate diets on the tumor microenvironment and immune infiltration. Therefore, intervening in metabolic disorders via VLCD to disrupt the insulin-PI3K axis and exploring its regulation of the tumor immune microenvironment represents a promising translational approach. Moreover, CD8+ T cells, as central effector cells in anti-tumor immunity, are positively correlated with prognosis in various cancers, but the mechanisms by which their infiltration in endometrial cancer is regulated by diet remain unclear.

 

 

Research Methods and Experiments

The study enrolled 19 women diagnosed with endometrial cancer and overweight or obesity, randomly assigned to either the VLCD group (n=13) or the standard diet (SD) group (n=6), with an intervention period of 21–28 days until surgery. The VLCD group received customized ketogenic meals from the research team, providing 87.2% of total energy from fat and only 6.2% from carbohydrates. All participants received weekly nutritional counseling, and adherence was assessed via meal consumption rates and urinary ketone testing. Systemic metabolic changes were evaluated by measuring fasting glucose, insulin, HbA1c, and lipid profiles. Tumor tissues were collected at biopsy and surgery for immunohistochemistry (IHC) and RNA sequencing analysis, focusing on p-AKT (Ser473), Ki-67, CD8+ T cell infiltration, and apoptosis marker CC3. RNA-Seq data were analyzed using GSEA to identify pathway alterations. This design effectively utilized the preoperative window, enhancing statistical power through both within-subject and between-group comparisons.

Key Conclusions and Perspectives

• Adherence in the VLCD group reached 91 ± 4%, with an average weight loss of 5.5 ± 0.8%, and no grade 3/4 adverse events occurred, indicating high feasibility and good tolerability of the diet in preoperative patients, supporting its use in future larger-scale clinical trials.
• Fasting insulin levels decreased by 60 ± 3.8% and glucose by 22 ± 5.9%, confirming that VLCD rapidly improves insulin resistance and reduces systemic activation of the PI3K pathway, suggesting its potential as an adjuvant therapy in PI3K-related tumors.
• Total cholesterol and LDL increased by 6 ± 2.7% and 17.8 ± 8.9%, respectively, indicating the need for lipid metabolism monitoring during long-term interventions to balance anti-tumor effects with cardiovascular risks.
• Both RNA-Seq and IHC revealed significant enrichment of CD8+ T cells at the tumor margin (q = 0.034; NES = 1.75), suggesting that VLCD may activate anti-tumor immunity through metabolic reprogramming, providing a mechanistic basis for combining immunotherapy with dietary intervention.
• p-AKT tumor staining was significantly reduced in the VLCD group, indicating that dietary intervention directly suppresses PI3K signaling activity within tumors, supporting a synergistic treatment strategy combining PI3K inhibitors with low-carbohydrate diets.
• Although Ki-67 and CC3 showed no significant changes, suggesting no major impact on proliferation or apoptosis during short-term intervention, the rapid remodeling of metabolic and immune microenvironments implies that longer intervention periods may yield more significant tumor control, warranting validation in subsequent animal models.

Research Significance and Prospects

This study is the first in human patients with endometrial cancer to demonstrate the positive regulatory effects of a very low-carbohydrate diet on the tumor immune microenvironment, particularly enhanced CD8+ T cell infiltration, providing direct clinical evidence for the interplay among 'metabolism-immunity-tumor.' This finding has important implications for drug development: future studies could explore VLCD as a sensitizer for PI3K inhibitors or immune checkpoint inhibitors, especially in obese patients with PI3K-mutated endometrial cancer.

From a clinical monitoring perspective, fasting insulin and ketone levels can serve as reliable biomarkers for dietary intervention and should be incorporated into routine monitoring in future trials. Additionally, heterogeneity in tumor molecular subtypes (e.g., POLE, MSI, CN-H) may influence dietary response, necessitating stratified analysis in future studies.

In terms of disease modeling, this study supports the development of humanized endometrial cancer models under obese conditions to test the combined efficacy of dietary and targeted therapies. Coupled with dynamic monitoring of CD8+ T cells, this can further elucidate how metabolic interventions reshape the immune landscape, advancing the field of precision nutritional oncology.

 

 

Conclusion

This study establishes the clinical feasibility and safety of a very low-carbohydrate ketogenic diet in treatment-naïve endometrial cancer patients with obesity. Through short-term intervention, VLCD not only significantly improved patients' metabolic status by reducing insulin and glucose levels but also unexpectedly activated anti-tumor immunity, evidenced by significant CD8+ T cell infiltration at the tumor margin. This finding reveals the potential value of metabolic intervention in reshaping the tumor microenvironment, suggesting that dietary patterns may become an important component of cancer adjuvant therapy. From bench to bedside, this study lays the foundation for larger randomized controlled trials, and future research should explore the combination of VLCD with PI3K inhibitors or immunotherapy, particularly in patients with PTEN loss or PIK3CA mutations. Meanwhile, standardized nutritional intervention protocols and response monitoring systems should be established, integrating 'precision nutrition' into the comprehensive management pathway for endometrial cancer. This work not only advances the field of nutritional oncology but also provides actionable clinical strategies to improve outcomes in patients with obesity-related cancers, holding significant public health implications.

 

Ezequiel Dantas, Katie C Hootman, Jenna Moyer, Vicky Makker, and Marcus D Goncalves. Very low-carbohydrate ketogenic diet in treatment-naïve women with endometrial cancer and overweight: a randomized feasibility study. Nature Communications.