circZNF148 Drives Glucose Metabolism Reprogramming to Enhance Metastasis and Immune Evasion via HK1 Stabilization in Triple‐Negative Breast Cancer

ABSTRACT

Breast cancer is the leading malignancy among women worldwide, with triple‐negative breast cancer (TNBC) representing the most aggressive subtype. Accumulating evidence highlights glucose metabolism reprogramming as a critical driver of TNBC progression and immune evasion, yet the underlying molecular mechanism remains poorly defined. Using circRNA sequencing in both glucose metabolism‐stressed TNBC cells and lung metastasis models, we identified circZNF148 as a consistently upregulated circular RNA that promotes tumor progression and immune evasion by enhancing glycolysis. Mechanistically, circZNF148 scaffolds the interaction between hexokinase 1 (HK1) and the deubiquitinase adaptor ADRM1, suppressing K11‐linked ubiquitination and proteasomal degradation of HK1, thereby stabilizing the enzyme and sustaining glycolytic flux. Elevated lactate production subsequently impairs CD8 ⁺ T cell function, reducing IFN‐γ and TNF‐α secretion, diminishing cytotoxicity, and promoting exhaustion. Concurrently, increased intracellular lactate drives lysine lactylation of PD‐L1, which enhances its protein stability and membrane localization, thus linking metabolic state to immune checkpoint regulation. Clinically, circZNF148 is significantly upregulated in TNBC tissues, correlating with advanced stage and poor prognosis. Collectively, our findings establish the circZNF148‐HK1‐lactate axis as a critical mediator of metabolic adaptation and immune evasion in TNBC. Targeting this pathway offers a promising strategy to overcome therapeutic resistance and improve outcomes in TNBC.