Breast cancer is made more aggressive by type 2 diabetes exosomes
Exosomes in diabetes can reprogram immune cells in tumors, allowing the cancer to grow and spread.
Tiny particles in the blood, known as exosomes, are altered by diabetes in a way that reprograms immune cells in the tumor environment making them weaker, allowing the cancer to grow and spread more aggressively.
There is much evidence that metabolic disorders including insulin resistance, metabolic syndrome, and type 2 diabetes increase breast cancer risk and mortality. Excess glucose availability and higher levels of insulin are growth promoters for cancer cells. Research just published in Nature Communications Biology reveals how exosomes in type 2 diabetes suppress immune cells in the tumor microenvironment (TME).
“Metabolic disorders, particularly Type 2 diabetes (T2D), raise concerns for the management of breast cancer. Population studies have shown that women with T2D have 40% increased risk of developing breast cancer and 74% increase in overall mortality compared to non-diabetic (ND) women1... Recently, investigations into the immune phenotype of T2D have described subclinical chronic inflammation that induces insulin resistance and metabolic dysfunction that accompany the disease2. This inflammatory milieu ultimately leads to T cell dysfunction3, posing a significant clinical challenge for breast cancer patients. Cancer cells have adaptations that allow them to exploit this dysfunction, reprogramming immune cells to evade detection and clearance4. Traditional molecular diagnostics fall short in capturing these profound differences seen in the tumor microenvironment (TME) of T2D1, highlighting an urgent need for improved diagnostic and therapeutic approaches.”
Exosomes
An exosome is a tiny, membrane-bound extracellular vesicle carrying biomolecules such as proteins, lipids, DNA, and various types of RNA from their cell of origin that play a crucial role in intercellular communication by transferring their molecular cargo, thereby influencing the behavior and function of recipient cells. Changes in exosomes are associated with various diseases and some are used for diagnostic purposes, especially for cancer.
“Our group and others have recently highlighted the critical role of exosomes in linking metabolic dysregulation with cancer pathophysiology5,6,7. We demonstrated that exosomes isolated from T2D patient adipocytes promote a more aggressive tumor phenotype in cellular models of breast cancer, increasing epithelial-to-mesenchymal transition (EMT) and cancer stem-like cell (CSC) formation, compared to ND controls8. Similarly, plasma-derived exosomes from T2D patients enhanced EMT and CSC traits in prostate cancer cell lines9.”
The tumor microenvironment (TME)
The tumor microenvironment is the complex ecosystem surrounding a tumor, consisting of cancer cells, various stromal cells (such as immune cells, fibroblasts, and blood vessel cells), signaling molecules, and the extracellular matrix. This environment is dynamic and continuously interacts with the tumor, playing an active role in supporting tumor growth, invasion, and progression. Promoting a TME that is as inhospitable as possible for cancer cells is a cardinal intent of case management in the function medicine model. “Take away as much as possible what tumor cells like and give them, as much as possible, what they don’t like.” They especially like glucose and insulin, and they very much dislike immune cells that actively attack them. They deploy a number of tactics to suppress immune cells in the TME.
“Within the breast TME, exosomes have emerged as key mediators of cellular communication…that influence tumor behavior and progression5.”
“Using a novel patient-derived organoid (PDO) system that preserves native tumor-infiltrating lymphocytes (TILs), we show that T2D plasma exosomes induce a 13.6-fold expansion of immunosuppressive TILs relative to nondiabetic controls. This immune dysfunction may promote micrometastatic survival and resistance to checkpoint blockade, a known issue in T2D cancer patients. Tumor-intrinsic analysis revealed a 1.5-fold increase in intratumoral heterogeneity and 2.3-fold upregulation of aggressive signaling networks. These findings reveal how T2D-associated metabolic dysregulation alters tumor–immune crosstalk through previously underappreciated exosomal signaling, impairing antitumor immunity and accelerating progression.”
Metabolic health must be a cornerstone of cancer managment
The authors discuss their important findings:
“T2D has long been established as a risk factor for poorer prognosis of breast cancer across numerous population studies1. Epidemiological data indicate that women with T2D have a higher incidence of breast cancer compared to ND and they often present with more aggressive tumor phenotypes27. Meta-analyses and large-cohort studies have reinforced these findings, suggesting that metabolic dysregulation in T2D may contribute to the pathogenesis and progression of breast cancer41. Much of the existing research has focused on tumor-intrinsic properties, including insulin-like growth factor signaling and excess glucose availability feeding tumor growth1. However, the role of the TME in this comorbidity has been largely overlooked. In this study, we aimed to investigate the impact of metabolic dysregulation in T2D on breast cancer aggressiveness and TME dynamics.”
Very interestingly…
“This reprogramming highlights a checkpoint-independent mechanism of T cell suppression, wherein ER [endoplasmic reticulum of the mitochondria] stress fundamentally redirects differentiation toward a dysfunctional state.”
Insulin resistance, metabolic syndrome, and type 2 diabetes all create persistent cellular stress that places a heavy burden on the endoplasmic reticulum (ER), disrupting its homeostasis and triggering maladaptive stress responses leading to insulin signaling impairment and cell dysfunction.
“Contrary to our expectations, we did not observe upregulation of checkpoint ligands on T cells, which would have indicated classical exhaustion. Immune exhaustion is a well-characterized mechanism of dysfunction in cancer, marked by sustained expression of inhibitory receptors and progressive loss of effector function4. While exhaustion phenotypes are known to worsen in T2D and contribute to poor clinical outcomes3, the immune profile observed here suggests a distinct, non-canonical pattern of T cell impairment. Our data instead point to ER stress as a central driver of T cell dysfunction.”
“These results have direct therapeutic implications. Standard immunotherapies that rely on checkpoint inhibition may be ineffective in this context, where T cells are not classically exhausted but rather reprogrammed by ER stress. This result is consistent with existing literature reporting a diminished response to immunotherapy in T2D cancer patients58,59.”
Moreover, the debris field resulting from cancer cell death from chemotherapy over time also induces a change in immune cells (macrophages) from an active ‘attack’ M1 type to a tolerant M2 type, adding to immunosuppression in the TME.
Clinical takeaway
The authors conclude:
“These findings reveal how T2D-associated metabolic dysregulation alters tumor–immune crosstalk through previously underappreciated exosomal signaling, impairing antitumor immunity and accelerating progression.”
“Our results suggest that metabolic status, particularly T2D, could be considered in the clinical management of estrogen receptor-positive breast cancer to improve therapeutic outcomes. Given the unique vulnerabilities of this population, we strongly advocate for the initiation of targeted clinical trials to explore the TME in these 120 million underserved and understudied patients. Addressing these gaps in knowledge and care could pave the way for more effective, personalized treatment strategies, ultimately improving survival and quality of life for this high-risk group.”
Technology Networks quotes corresponding author Gerald Denis, PhD, the Shipley Prostate Cancer Research Professor at Boston University:
“Breast cancer is already challenging to treat, and people with type 2 diabetes have worse outcomes, but clinicians don’t fully understand why,” said Denis. “Our study reveals one possible reason: diabetes changes the way the immune system works inside tumors. This could help explain why current treatments, like immunotherapy, don’t work as well in patients with diabetes. Knowing this opens the door to better, more personalized treatments for millions of people. Over 120 million Americans are diabetic or prediabetic, yet if they develop cancer, they are not treated differently in any significant way by the standards of treatment in oncology. Thus, this work addresses a serious public health challenge.”
