MCT4 deficiency suppresses tumor incidence and metastasis by downregulating IGF1 expression and enhancing anti-tumor immunity.

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.