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Abstract Hypoxia and high accumulation of lactic acid in the tumor microenvironment provide fertile soil for tumor development, maintenance and metastasis. Herein, we developed a calcium peroxide (CaO 2 )-loaded nanostructure that can play a role of “one stone kill two birds”, i.e., acidic and hypoxic tumor microenvironment can be simultaneously regulated by CaO 2 loaded nanostructure. Specifically, CaO 2 -loaded mesoporous polydopamine nanoparticles modified with sodium hyaluronate (denoted as CaO 2 @mPDA-SH) can gradually accumulate in a tumor site. CaO 2 exposed in acidic microenvironment can succeed in consuming the lactic acid with oxygen generation simultaneously, which could remodel the acid and hypoxia tumor microenvironment. More importantly, the relief of hypoxia could further reduce lactate production from the source by down-regulating the hypoxia inducible factor-1α (HIF-1α), which further down-regulated the glycolysis associated enzymes including glycolysis-related glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). As a result, CaO 2 @mPDA-SH alone without the employment of other therapeutics can dually regulate the tumor hypoxia and lactic acid metabolism, which efficiently represses tumor progression in promoting immune activation, antitumor metastasis, and anti-angiogenesis.
Ruan et al. (Wed,) studied this question.