The Warburg effect as a metabolic niche construction strategy in the tumor microenvironment

Abstract

The advantage conferred by the Warburg effect to cancer cells remains unresolved. While extensive research has examined aerobic glycolysis at the intracellular level, emphasizing its possible biosynthetic or ATP-production rate benefits, the fate of the energy-rich lactate exported into the tumor microenvironment (TME) has received comparatively little attention. Yet lactate is far from metabolically inert: it actively shapes the TME, functioning as a toxin to adaptive immune cells and simultaneously promoting growth of several non-cancerous cells in the tumor microenvironment which in turn promote tumor growth. Here, we develop a minimal consumer-resource model incorporating tumor, anti-tumor immune, and pro-tumor stromal populations interacting through shared nutrients, lactate, and metabolic byproducts. We find that lactate secretion imposes a growth-exclusion tradeoff: higher glycolytic allocation suppresses anti-tumor immune cells but simultaneously reduces tumor abundance due to less efficient metabolism. This tradeoff is resolved in the presence of pro-tumor stromal populations capable of metabolic cross-feeding, namely stromal cells that convert lactate into metabolites which feed back to support tumor growth, thereby offsetting the glycolytic cost. The cross-feeding benefit is second-order in population size, requiring a critical tumor mass to operate. Taken together, these results suggest that there may be an ecological advantage of the Warburg effect, contingent on microenvironmental context. Specifically, lactate secretion is beneficial primarily when appropriate stromal partners are present, functioning as a niche-construction strategy that reorganizes the tumor ecosystem in favor of tumor expansion.