Targeting the Warburg Effect in Cancer: Where Do We Stand?

Abstract

Warburg effect; Aerobic glycolysis; Tumor metabolism

Efecto Warburg; Glucólisis aeróbica; Metabolismo tumoral

Efecte Warburg; Glucòlisi aeròbica; Metabolisme tumoral

The Warburg effect, characterized by the preferential conversion of glucose to lactate even in the presence of oxygen and functional mitochondria, is a prominent metabolic hallmark of cancer cells and has emerged as a promising therapeutic target for cancer therapy. Elevated lactate levels and acidic pH within the tumor microenvironment (TME) resulting from glycolytic profoundly impact various cellular populations, including macrophage reprogramming and impairment of T-cell functionality. Altogether, the Warburg effect has been shown to promote tumor progression and immunosuppression through multiple mechanisms. This review provides an overview of the current understanding of the Warburg effect in cancer and its implications. We summarize recent pharmacological strategies aimed at targeting glycolytic enzymes, highlighting the challenges encountered in achieving therapeutic efficacy. Additionally, we examine the utility of the Warburg effect as an early diagnostic tool. Finally, we discuss the multifaceted roles of lactate within the TME, emphasizing its potential as a therapeutic target to disrupt metabolic interactions between tumor and immune cells, thereby enhancing anti-tumor immunity.

The study was undertaken with the support of the Fundación Asociación Española contra el Cáncer (AECC), the ISCIII, FIS (PI22/00130), BBVA (CAIMI), and Cellex Foundation.