MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Inactivating STK11/LKB1 mutations are key drivers of primary resistance to immunotherapy in KRAS-mutated lung adenocarcinoma (LUAD).
• The precise mechanisms underlying this resistance are not fully understood.

Purpose of the Study:

• To elucidate the mechanisms by which STK11/LKB1 mutations confer resistance to immunotherapy in LUAD.
• To investigate the role of lactate and its associated pathways in mediating immune suppression in LUAD.
• To explore therapeutic strategies targeting lactate metabolism for overcoming immunotherapy resistance.

Main Methods:

• Single-cell RNA profiling of murine models with LKB1 loss.
• Analysis of lactate production and secretion via the MCT4 transporter.
• Assessment of immune cell polarization (M2 macrophages) and T cell function.
• In vivo studies using syngeneic murine models with MCT4 knockout or GPR81 blockade.
• Analysis of tumor samples from STK11/LKB1 mutant LUAD patients.

Main Results:

• LKB1 loss enhances lactate production and secretion mediated by the MCT4 transporter.
• LKB1-deficient tumors exhibit increased M2 macrophage polarization and hypofunctional T cells.
• Exogenous lactate recapitulates these immune suppressive effects, while MCT4 knockdown or GPR81 blockade abrogates them.
• MCT4 knockout reverses PD-1 blockade resistance caused by LKB1 loss.
• Human STK11/LKB1 mutant LUAD tumors show similar immune phenotypes.

Conclusions:

• Lactate suppresses anti-tumor immunity by promoting M2 macrophage polarization and T cell dysfunction.
• Targeting the lactate pathway (MCT4, GPR81) is a promising strategy to reverse immunotherapy resistance in STK11/LKB1 mutant LUAD.
• This study provides a mechanistic link between LKB1 status, lactate metabolism, and immune evasion in lung cancer.