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 tumorinfiltrating 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 tumorinfiltrating 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.
Lung cancer is one of the most fatal cancers worldwide. Resistance to conventional therapies remains a hindrance to patient treatment. Therefore, the development of more effective anti-cancer therapeutic strategies is imperative. Solid tumors exhibit a hyperglycolytic phenotype, leading to enhanced lactate production; and, consequently, its extrusion to the tumor microenvironment. Previous data reveals that inhibition of CD147, the chaperone of lactate transporters (MCTs), decreases lactate export in lung cancer cells and sensitizes them to phenformin, leading to a drastic decrease in cell growth. In this study, the development of anti-CD147 targeted liposomes (LUVs) carrying phenformin is envisioned, and their efficacy is evaluated to eliminate lung cancer cells. Herein, the therapeutic effect of free phenformin and anti-CD147 antibody, as well as the efficacy of anti-CD147 LUVs carrying phenformin on A549, H292, and PC-9 cell growth, metabolism, and invasion, are evaluated. Data reveals that phenformin decreases 2D and 3D-cancer cell growth and that the anti-CD147 antibody reduces cell invasion. Importantly, anti-CD147 LUVs carrying phenformin are internalized by cancer cells and impaired lung cancer cell growth in vitro and in vivo. Overall, these results provide evidence for the effectiveness of anti-CD147 LUVs carrying phenformin in compromising lung cancer cell aggressiveness.
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