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<p>Monocarboxylate transporter 4 (MCT4/<i>SLC16A3</i>) 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<sup>-/-</sup>) using CRISPR/Cas9-EGE technology. Compared with wild-type counterparts, MCT4<sup>-/-</sup> 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<sup>-/-</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Shuo Wang,
  • Hailing Guo,
  • Lujin Feng,
  • Xinyi Wang,
  • Yujie Zhang,
  • Xin Li,
  • Xiaoju Zhou,
  • Ningning Ma

摘要

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.