Use of Splenda Counteracts Immunotherapy Benefits by Altering Gut Bacteria

Background 

"We are what we eat."

We are all familiar with this age-old saying that highlights the importance of a balanced diet. It has long been known that the food we eat directly influences not only our health but also our happiness.

A healthy lifestyle also includes the ability of our immune system to defend us against deadly diseases, including cancer. Recent research highlights how a popular sugar substitute - Splenda- affects our ability to fight cancers. Splenda impacts the gut bacterial composition, leading to the release of bacterial metabolites that impair the immune system's ability to fight tumor growth.

This article describes this study in detail, piecing together different pieces of a puzzle that were previously unclear.

Cancer and Immunotherapy

Cancer remains a leading cause of death worldwide. According to the WHO, about 1 in 5 people will develop cancer during their lifetime. Immunotherapy is a treatment that activates the immune system to combat cancer. Immune checkpoint inhibitors (ICIs) are the most commonly used immunotherapy treatment. They work by blocking checkpoint proteins that are masked by cancer cells to evade the immune system.

One such checkpoint protein is the PD-1 receptor expressed by T-cells, which is essential for proper T-cell activation. Cancer cells deactivate T-cells by expressing the PD-1 ligand (PD-L1). ICIs with an anti-PD-1 antibody function by preventing this interaction, thereby reactivating T-cells to generate a better anticancer response.

Fig 1: Pictorial representation of T-cell inhibition and activation by tumor expressing PD-L1 and anti-PD-1 checkpoint therapy, respectively.²

The problem - Although highly effective in skin and lung cancers, ICIs are less effective with other types of cancers. The differences in reactivity have been linked to many factors, among which diet plays a significant role.

Role of Diet and Gut Microbiota in Immunity

The gut contains millions of bacteria, and their composition depends on the type of food we eat. A healthy and diverse gut microbiota supports overall health and wellness. This helps prevent unnecessary inflammation and maintain homeostasis. Importantly, gut bacteria produce various metabolites after digesting food. Some of these metabolites directly influence immune cells in the body, including T-cells that play a key role in anti-cancer immunity.

Rise of Splenda (Active ingredient -Sucralose) as a Sugar Substitute

Sucralose is one of the most popular sugar substitutes in the U.S. A taste profile similar to sugar, ease of mixing into many foods and drinks, and low calories are the main reasons why Splenda is popular among consumers. Studies show their impact on gut bacteria and T-cell function.

A 2017 study showed that 7 days of high-dose sucralose consumption did not affect gut bacteria in healthy adults.³ However, another group reported that 10 weeks of high-dose sucralose induced gut dysbiosis.⁴ Interestingly, studies in mice showed that high doses of sucralose affected T-cell proliferation and differentiation, reducing its anti-tumor effects.⁵ Therefore, it is becoming increasingly clear that prolonged consumption of sucralose can harm immune responses.

The Gap - Is there a link between Splenda consumption and T-cell inactivation in Cancer Immunotherapy?

Sucralose in Cancer Immunotherapy

To explore how sucralose might affect cancer immunotherapy, scientists studied patients with two types of cancers - skin cancer and lung cancer, who were receiving immunotherapy with anti-PD1. The study focused on two key outcomes. One, called the Objective Response Rate (ORR), looked at the percentage of patients whose tumors either shrank significantly or disappeared after treatment. The other, known as progression-free survival (PFS), measured how long patients remained free from their disease worsening following treatment.

This study found that a high daily intake of sucralose reduced both PFS and ORR. This indicated that sucralose negatively affected the effectiveness of anti-PD1 immunotherapy in the cancers tested.

Similar results were observed in mouse models of cancer. Mouse models allow easier experiments to determine mechanistic links to the observed effects. Researchers first looked at changes to CD8 T-cells that might explain the reduced effectiveness of ICI. As expected, mice consuming sucralose had dysfunctional T-cells.

What causes CD8 T cells to be dysfunctional in sucralose-consuming mice?

To explore this question, scientists repeated the same experiment using mice from two different sources. Although these mice are genetically identical, their gut microbiota differ, which made the study even more interesting! They noticed that the mice responded differently to immunotherapy depending on their microbiota, suggesting that gut bacteria might influence T-cell health. Further investigation showed that sucralose tends to boost the growth of harmful bacteria in the gut. This shift in bacterial populations causes a drop in arginine, an essential amino acid for T-cell function. This research helps us understand how sucralose consumption could be linked to the reduced effectiveness of immunotherapy effects.

Bottom Line

This study highlights how vital our diet is in supporting our immune system, especially when it comes to fighting cancer. Splenda, a popular sugar substitute found in many drinks, desserts, and candies, can disturb the balance of good bacteria in our gut, leading to less effective T-cells. When T-cells don't function optimally, it can make immunotherapy less successful for cancer patients.

References

1.          Morder, K.M. et al. (2025) ‘Sucralose consumption ablates cancer immunotherapy response through microbiome disruption.’, Cancer Discovery, doi:10.1158/2159-8290.cd-25-0247

2.          Marei, H. E., Hasan, A., Pozzoli, G. & Cenciarelli, C. Cancer immunotherapy with immune checkpoint inhibitors (ICIs): potential, mechanisms of resistance, and strategies for reinvigorating T cell responsiveness when resistance is acquired. Cancer Cell Int 23, 64 (2023).

3.          Thomson, P., Santibañez, R., Aguirre, C., Galgani, J. E. & Garrido, D. Short-term impact of sucralose consumption on the metabolic response and gut microbiome of healthy adults. British Journal of Nutrition 122, 856–862 (2019).

4.          Méndez-García, L. A. et al. Ten-Week Sucralose Consumption Induces Gut Dysbiosis and Altered Glucose and Insulin Levels in Healthy Young Adults. Microorganisms 10, 434 (2022).

5.          Zani, F. et al. The dietary sweetener sucralose is a negative modulator of T cell-mediated responses. Nature 615, 705–711 (2023).

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