MCT4 缺陷通过下调 IGF1 表达和增强抗肿瘤免疫来抑制肿瘤发生和转移

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.