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Studies have reported that tumor cell–derived lactate, which lowers the pH of TME to values below 6-6.5, is able to render T lymphocytes anergic due to reduced cytokine secretion including IFN-γ, IL-2, and TNF-α, decreased expression of TCR and IL-2 receptor CD25, as well as impairment of STAT5 and ERK activation after TCR binding