Uncontrolled hyperglycemia-induced membrane cholesterol dysregulation drives tumor immune evasion by reducing hardness of tumor cell plasma membrane

Suboptimal glycemic control facilitates tumor immune evasion, severely impairing the prognosis of patients with cancer. Tumor cell softness, a critical biomechanical property, is closely associated with cell proliferation, migration, and immune cell interactions, thereby regulating tumor progression. However, whether blood glucose induces immune evasion by modulating tumor cell hardness—defined as a "physical property immune checkpoint"—and its underlying mechanisms remain unclear. This study demonstrates that elevated glucose concentrations in culture systems progressively soften tumor cells, reducing the cytotoxicity of CD8 + T cells. Specifically, glucose increases cytoplasmic and plasma membrane cholesterol levels in tumor cells, reducing cellular hardness. Mechanistically, hyperglycemia disrupts DNA methylation in tumor cells: dysregulated expression of DNA methyltransferase DNMT3A and demethylase TET2 enhances methylation of the cholesterol efflux gene ABCA1 promoter, downregulating ABCA1. Impaired ABCA1 hinders cholesterol efflux, causing intracellular accumulation, increasing plasma membrane cholesterol, softening cells, and weakening T-cell cytotoxicity. Additionally, BCL11B binds the ABCA1 promoter, recruiting DNMT3A and TET2 to regulate methylation. In conclusion, this study identifies glucose-mediated modulation of the tumor cell membrane-force axis in immune evasion, clarifies the links between hyperglycemia-induced DNA methylation dysregulation, aberrant cholesterol accumulation and the cell hardness, contributing to the poor prognosis of cancer patients with suboptimal glycemic control from a biomechanical perspective. Schematic Illustration of the Proposed Underlying Mechanism Elucidating How Uncontrolled Hyperglycemia Leads to Tumor Immune Evasion via Reducing Cell Membrane Stiffness • Uncontrolled hyperglycemia enhances immune evasion and tumor progression. • Glucose weakens the killing effect of T cells by softening the plasma membrane of tumor cells. • The elevated methylation level in the promoter region of ABCA1 caused by high glucose reduces the expression of ABCA1, resulting in the accumulation of cholesterol in the plasma membrane. • This study indicates that the tumor cell membrane hardness is a crucial factor linking hyperglycemia with tumor immune evasion.