Loss of LATS1 promotes immune evasion in colon cancer via YAP/TEAD-driven lactate metabolism reprogramming
TL;DR
A novel LATS1–LDHA–lactate axis that drives immune evasion in colon cancer through metabolic remodeling is identified, highlighting LATS1 as a potential therapeutic target for enhancing anti-tumor immunity.
Abstract
The Hippo pathway components YAP and TAZ have been implicated in tumor immunity, but the role of upstream kinase LATS1 in colon cancer immune evasion remains unclear. This study aimed to investigate the function of LATS1 in regulating the tumor immune microenvironment (TME) of colon cancer. Human colon cancer tissues were analyzed to compare LATS1 expression levels with adjacent normal tissues, and survival analysis was performed using Kaplan-Meier curves with log-rank test. MC38 cells with LATS1 knockdown were established and transplanted into immunocompetent and immunodeficient mice to assess tumor growth. Mitochondrial fission was measured by immunofluorescence, reactive oxygen species (ROS) levels were detected by flow cytometry, and lactate dehydrogenase A (LDHA) expression and lactate accumulation were quantified by Western blot and biochemical assays respectively. Intratumoral immune cell infiltration and function were analyzed by flow cytometry. The LDHA inhibitor FX-11 was used for pharmacological intervention studies. LATS1 was significantly downregulated in human colon cancer tissues compared to normal adjacent tissues, and this downregulation correlated with poor patient prognosis. LATS1 knockdown enhanced tumor growth in immunocompetent but not immunodeficient mice. Mechanistically, LATS1 deficiency promoted mitochondrial fission, increased ROS production, upregulated LDHA expression, and enhanced lactate accumulation. This metabolic reprogramming created an immunosuppressive TME characterized by reduced NK cell infiltration and impaired CD8⁺ T cell effector function. Pharmacological inhibition of LDHA with FX-11 reversed these effects, restoring NK cell infiltration and cytokine production while suppressing tumor growth. Our study identifies a novel LATS1–LDHA–lactate axis that drives immune evasion in colon cancer through metabolic remodeling, highlighting LATS1 as a potential therapeutic target for enhancing anti-tumor immunity.