Lactate as a Regulator of Cancer Inflammation and Immunity

Resistance to anti-cancer therapies is a consequence of adaptation of cancer cells but also of maladaptation of tumor-infiltrating immune cells. The opposing roles acquired by the immune system have to be faced in order to fight tumor growth and therapy resistance. Effector immune cells are recruited and activated but they are blocked by the strong immunosuppressive nature of the tumor microenvironment (TME). Immune evasion and deregulation of energy metabolism are two hallmarks of cancer that may be functionally linked. Malignant cells which present a high glycolytic phenotype, besides creating metabolic demanding environments that encroach on the function of tumor-infiltrating immune cells, also release immunosuppressive metabolites and by-products, such as lactate, forming a metabolic symbiosis with immune cells. This acidic TME has a strong impact in the profile of tumor-infiltrating immune cells, being instrumental for immunosuppression. Therefore, in this review, we focus on key molecular mechanisms by which lactate metabolically modulates immune cell response during tumor development and progression.