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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\u2010related factors (Bax\/Bcl\u20102, caspase), and glycolysis pathways (e.g., GLUT\u20101, PKM2, PFK, HK2, MCT\u20101, and LDH). Lactate metabolism, in turn, is interconnected with several dysregulated signaling mediators, including PI3K\/Akt\/mTOR, AMPK, NF\u2010\u03baB, Nrf2, JAK\/STAT, and HIF\u20101\u03b1. 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\u2010target alternative compounds with health\u2010promoting properties possess more high effectiveness and low side effects than conventional agents. Besides, the mechanism of multi\u2010targeted natural sources is related to lactate production and cancer\u2010associated cross\u2010talked factors. This review focuses on targeting the lactate metabolism\/transporters, and lactate\u2010associated mediators, including glycolytic pathways. Besides, interconnected mediators to lactate metabolism are also targeted by natural products. Accordingly, plant\u2010derived secondary metabolites are introduced as alternative therapies in combating cancer through modulating lactate metabolism and glycolytic pathways.<\/jats:p>","DOI":"10.1002\/biof.1799","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T13:09:53Z","timestamp":1635772193000},"page":"359-383","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Targeting lactate metabolism and glycolytic pathways in the tumor microenvironment by natural products: A promising strategy in combating cancer"],"prefix":"10.1002","volume":"48","author":[{"given":"Leila","family":"Kooshki","sequence":"first","affiliation":[{"name":"Student Research Committee Kermanshah University of Medical Sciences  Kermanshah Iran"},{"name":"USERN Office Kermanshah University of Medical Sciences  Kermanshah 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