Cancer cells exhibit a distinctive metabolic profile, often characterized by high glucose uptake and fermentation, a phenomenon known as the Warburg effect. This process, while inefficient in ATP production compared to mitochondrial respiration, provides necessary metabolites for macromolecule biosynthesis. The Warburg effect is a hallmark of many cancers, and glucose uptake, mediated by glucose transporters (GLUTs), is a rate-limiting step. Hypoxia, a common feature of the tumor microenvironment (TME), upregulates GLUT1 expression, further enhancing glycolysis. The accumulation of lactic acid contributes to acidosis in the TME. Brown adipose tissue (BAT), specialized for thermogenesis through non-shivering thermogenesis (NST), utilizes glucose in its heat-generating process. Cold exposure activates BAT, increasing glucose uptake. This study investigates the impact of cold-induced BAT activation on tumor growth, exploring the interplay between global metabolic changes and cancer progression. The researchers hypothesized that cold exposure, by activating BAT and thereby decreasing blood glucose levels, would inhibit tumor growth by limiting the fuel supply for cancer cell glycolysis.

The paper extensively reviews existing literature on cancer metabolism, particularly the Warburg effect and its significance in tumor growth and metastasis. It highlights the roles of glucose transporters (GLUTs), especially GLUT1, in mediating glucose uptake by cancer cells. The influence of hypoxia and hypoxia-inducible factor-1α (HIF-1α) on GLUT1 expression is discussed. The literature also covers the metabolic characteristics of brown adipose tissue (BAT), including its role in thermogenesis and glucose utilization. The activation of BAT through cold exposure or pharmacological interventions, and its potential for treating metabolic disorders such as obesity and type 2 diabetes, is reviewed. The authors point to existing research on the link between altered lipid metabolism and cancer progression, acknowledging that changes in lipid metabolism can significantly impact tumor growth rates, metastasis, and drug responses.

The study employed multiple in vivo and in vitro models to investigate the effects of cold exposure on tumor growth. Initially, subcutaneous xenograft models of colorectal cancer (CRC) were established in immunocompetent C57BL/6 mice. Mice were exposed to different temperatures (4°C, 22°C, and 30°C) to determine the impact of cold on tumor growth and survival. Immunofluorescence staining was used to analyze various aspects of the TME, including hypoxia (CA9), proliferation (Ki-67), angiogenesis (CD31), and apoptosis (cleaved caspase 3). The same approach was used to study other tumor types including fibrosarcoma, breast cancer, melanoma, and pancreatic ductal adenocarcinoma. Two genetic spontaneous tumor models, MMTV-PyMT (breast cancer) and ApcMin (intestinal adenoma), were also employed to assess the effect of cold exposure. Positron emission tomography-computed tomography (PET-CT) imaging using 18F-fluorodeoxyglucose (18F-FDG) was used to monitor glucose uptake in BAT and tumors under both thermoneutral and cold conditions. Surgical removal of BAT and genetic deletion of Ucp1 were performed to elucidate the role of BAT in cold-induced tumor suppression. To further examine whether changes in blood glucose levels were the main mechanism underlying the observed effects, the researchers conducted experiments using high-glucose feeding in the drinking water. Finally, a pilot study on healthy volunteers and a cancer patient investigated the effect of mild cold exposure on BAT activation in humans. Metabolic analyses, including RNA sequencing and metabolomics, were employed to investigate metabolic reprogramming in tumors.

Exposure of tumor-bearing mice to 4°C significantly inhibited the growth of various solid tumors, including pancreatic cancer. This effect was reversed by removing BAT or by feeding mice a high-glucose diet. Genetic deletion of Ucp1, essential for BAT thermogenesis, also ablated the cold-induced anticancer effect. PET-CT imaging revealed a marked decrease in glucose uptake by tumors under cold exposure and a corresponding increase in glucose uptake by BAT. Cold exposure led to a significant decrease in blood glucose levels and improved insulin sensitivity in tumor-bearing mice. Mechanistically, cold exposure suppressed glycolysis in tumors by downregulating GLUT1, GLUT4, and GLUT7 expression, while upregulating these in BAT. Activation of PI3K, AKT, and mTOR signaling pathways was markedly inhibited in cold-exposed tumors. In a pilot study in humans, mild cold exposure significantly activated BAT in healthy individuals and a cancer patient. Simultaneously, a reduction in glucose uptake was observed in the tumor tissue of the cancer patient. The observed tumor growth inhibition was shown to be independent of direct local temperature changes in the tumor itself. The effect was also observed with internally-implanted tumors.

The study's findings demonstrate that cold-induced activation of BAT plays a crucial role in suppressing tumor growth by competing with tumors for glucose. The reduction in blood glucose levels caused by increased glucose uptake in BAT limits the fuel supply available for cancer cell glycolysis, thereby hindering tumor growth. The observed metabolic reprogramming in tumors, including the downregulation of GLUTs and inhibition of PI3K/AKT/mTOR signaling, further contributes to the anti-tumor effect. The successful replication of these findings across multiple tumor types and in genetic spontaneous tumor models strengthens the generalizability of the findings. The pilot study in humans provides initial evidence of the clinical relevance of this approach. This study provides a novel therapeutic strategy for cancer treatment by harnessing the metabolic capacity of BAT. The simplicity, low cost, and potential feasibility of this approach across various settings suggests wide applicability.

This study presents a novel paradigm for cancer therapy by activating brown adipose tissue (BAT) through cold exposure. The resulting competition for glucose between BAT and tumors effectively limits the fuel supply for cancer cell growth, significantly inhibiting tumor development. This simple and effective approach shows promise for various cancer types and warrants further investigation in rigorous clinical trials to validate its efficacy and safety in human patients. Future research should focus on optimizing cold exposure protocols, exploring combination therapies with other anticancer treatments, and further investigating the underlying mechanisms of BAT-mediated tumor suppression.

The study's primary limitation is the relatively small sample size in the human pilot study, limiting the generalizability of those findings. Further, while the authors rigorously attempt to rule out the possibility that direct cooling of the tumor is the mechanism of action, it is difficult to completely eliminate this possibility. Additional studies are needed to confirm the findings across diverse populations and tumor types. While mechanisms of action are proposed, further research is needed to fully understand the intricate metabolic pathways involved in BAT-mediated tumor suppression and the interactions between BAT, other adipose tissues, and the TME.