Exercise-induced lactate suppresses ccRCC via CNDP2-mediated depletion of intracellular amino acids

Abstract Although epidemiological evidence has established a link between physical exercise and reduced risk and recurrence of multiple cancers, the association between physical exercise and cancer risk varies depending on the cancer site. Therefore, there is an urgent need to explore the molecular mechanisms underlying the antitumor effects of exercise to identify which types of cancers can benefit the most from physical exercise. Recent studies have shown that amino acids and exercise-induced lactate can be used by Carnosine Dipeptidase 2 (CNDP2) to synthesize lactoyl amino acids (Lac-AAs), which are then immediately secreted. Thus, we propose that lactate can deplete intracellular amino acids in a CNDP2-dependent manner, thereby exerting antitumor effects. Further bioinformatics analysis revealed that clear cell renal cell carcinoma (ccRCC) has the highest CNDP2 expression level among the 33 types of cancer tissues. Therefore, we focused on the inhibitory effects of lactate in this type of cancer and indeed confirmed its inhibitory roles in both cell and animal models. This study not only provides compelling evidence for the anti-cancer effects of physical exercise in ccRCC, but also provides novel insights into the biological role of lactate in the tumor microenvironment and offers potential therapeutic opportunities for mechanism-based treatment of ccRCC.