Metabolites and the tumor microenvironment: From cellular mechanisms to systemic metabolism Original paper

What was studied?

This review delves into the complex relationship between the tumor microenvironment (TME) and metabolic processes that sustain cancer growth. It investigates how tumor cells adapt their metabolism to survive in the hostile and nutrient-deprived conditions within the TME. The review specifically highlights metabolic reprogramming, with a focus on how cancer cells modify their use of nutrients like glucose, glutamine, and fatty acids to fuel their proliferation and survival. The authors discuss how tumors exploit local metabolites, how the metabolic landscape affects immune cell function, and the challenges this poses for cancer treatment. Additionally, the review emphasizes the role of systemic metabolism and how diet, metabolic pathways, and external factors such as obesity or hormonal signaling influence tumor behavior.

Who was studied?

The review draws on a range of studies examining the metabolic changes in different cancer types, including breast, colorectal, lung, and pancreatic cancers. It discusses research on cancer cells, immune cells, and stromal cells within the TME. The research reviewed also focuses on the metabolic cross-talk between cancer cells and non-cancerous cells, such as immune cells (e.g., macrophages, T cells) and stromal cells (e.g., fibroblasts, adipocytes), highlighting the reciprocal effects these interactions have on metabolic pathways in the TME.

Most important findings

The review identifies several crucial findings regarding metabolic adaptations in the TME. Tumor cells often shift to aerobic glycolysis, known as the Warburg effect, to meet their high energy demands and to produce building blocks for rapid growth. However, the review also highlights that this metabolic shift is not universal across all cancer types, as tumors adapt to the unique nutrient availability in their specific environment. The TME is characterized by metabolic competition, where immune cells and cancer cells compete for limited resources like glucose and amino acids, impacting immune cell function and tumor growth. Tumor-associated macrophages (TAMs) were also found to play a pivotal role in shaping the metabolic landscape, with their polarization towards pro-tumoral M2 phenotypes being driven by metabolic factors such as lactate and glutamine. In addition, the review discusses how systemic metabolism can affect the local metabolic environment of tumors.

Key implications

The findings have significant therapeutic implications, especially in the context of targeting tumor metabolism for cancer treatment. Understanding how cancer cells reprogram their metabolism to exploit local nutrient conditions opens up opportunities for targeted therapies aimed at disrupting these metabolic pathways. The review also suggests that manipulating the TME’s metabolic environment—through dietary interventions, drugs targeting metabolic enzymes, or immune modulation—could enhance the effectiveness of cancer therapies, especially immunotherapy. Moreover, the study highlights the need for more research into the metabolic cross-talk between tumor cells, immune cells, and stromal cells to develop comprehensive strategies that target multiple facets of the TME simultaneously. The findings also point to the importance of considering the systemic metabolic state of the patient when designing personalized treatment plans, emphasizing the role of metabolic vulnerabilities in specific tumor types and patient conditions.