Anticancer drugs are not purely effective because of their toxicity, side effects, high cost, inaccessibility, and associated resistance. On the other hand,
cancer is a complex public health problem that could intelligently adopt different signaling pathways and alter the body's metabolism to escape from the immune system. One of the
cancer strategies to metastasize is modifying pH in the tumor microenvironment, ranging between 6.5 and 6.9. As a powerful determiner,
lactate is responsible for this
acidosis. It is involved in immune stimulation, including innate and adaptive immunity, apoptotic-related factors (Bax/Bcl-2,
caspase), and glycolysis pathways (e.g., GLUT-1, PKM2, PFK, HK2, MCT-1, and LDH).
Lactate metabolism, in turn, is interconnected with several dysregulated signaling mediators, including PI3K/Akt/mTOR, AMPK, NF-κB, Nrf2, JAK/STAT, and HIF-1α. Because of
lactate's emerging and critical role, targeting
lactate production and its transporters is important for preventing and managing
tumorigenesis. Hence, exploring and developing novel promising
anticancer agents to minimize human
cancers is urgent. Based on numerous studies, natural secondary metabolites as multi-target alternative compounds with health-promoting properties possess more high effectiveness and low side effects than conventional agents. Besides, the mechanism of multi-targeted natural sources is related to
lactate production and
cancer-associated cross-talked factors. This review focuses on targeting the
lactate metabolism/transporters, and
lactate-associated mediators, including glycolytic pathways. Besides, interconnected mediators to
lactate metabolism are also targeted by natural products. Accordingly, plant-derived secondary metabolites are introduced as
alternative therapies in combating
cancer through modulating
lactate metabolism and glycolytic pathways.