Monocarboxylate transporter 4 (MCT4/SLC16A3) is frequently upregulated in human cancers and associated with aggressive progression and poor clinical outcomes. To elucidate its functional role, we establish MCT4 homozygous knockout BALB/c mice (MCT4-/-) using CRISPR/Cas9-EGE technology. Compared with wild-type counterparts, MCT4-/- mice exhibit ~40% reduction in allograft tumor volume, which is partly attributable to diminished IGF1 production, as circulating and tumor interstitial IGF1 levels decrease by 40–45%. Exogenous IGF1 supplementation restores tumor growth, confirming this dependency. Moreover, MCT4 deficiency enhances antitumor immunity, characterized by increased infiltration of CD4⁺ and CD8⁺ T cells, NK cells, and macrophages, with a pronounced shift from immunosuppressive M2 to pro-inflammatory M1 macrophages. Consistently, across three independent carcinogenesis models (breast, lung, oral squamous cancers), MCT4-/- mice develop fewer and smaller lesions, underscoring its critical role in tumor incidence. Collectively, these findings identify MCT4 as a key driver of carcinogenesis through IGF1 regulation and immune modulation, highlighting its therapeutic potential. MCT4 (SLC16A3) deficiency suppresses tumor incidence and metastasis through IGF1 downregulation and immune activation highlighting its potential as a metabolic-immune therapeutic target.
Wang et al. (Mon,) studied this question.
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