Cholesterol in hematological malignancies: metabolism, mechanisms, and clinical implications

Abstract

Cholesterol is an amphiphilic molecule that is essential for maintaining membrane structure and integrity, serves as a precursor for steroid hormone synthesis, and plays a critical role in metabolic homeostasis and physiological function. In recent years, dysregulated cholesterol metabolism has emerged as a major focus of research in the field of hematological malignancies. A growing body of clinical evidence indicates that hypocholesterolemia is a common concomitant condition in various hematological malignancies and is closely associated with disease onset, progression, therapeutic response, and clinical outcomes. The mechanisms underlying tumor-associated hypocholesterolemia are complex and likely involve dysregulation of lipoprotein metabolism, liver dysfunction caused by systemic inflammatory responses, and abnormal cholesterol uptake and efflux by tumor cells, which collectively contribute to the exacerbation of hypocholesterolemia. In turn, this metabolic signature not only promotes tumor cell proliferation and enhances the potential for therapy resistance, but also reprograms the immune microenvironment by inducing T cell dysfunction and M2-like macrophage polarization. Emerging therapeutic strategies targeting cholesterol metabolism have shown promise in preclinical models. By providing a theoretical foundation, these strategies offer potential avenues for improving the early diagnosis and risk stratification of hematological malignancies and for developing innovative treatment regimens. In this review, we outline the biosynthesis, uptake, excretion, transformation, and regulatory networks of cholesterol; describe the specific alterations in cholesterol levels across different subtypes of hematological malignancies; elucidate the molecular mechanisms underlying hypocholesterolemia; and explore its effects on tumor cell biology and the immune microenvironment, as well as its clinical significance, with the aim of providing new perspectives for related treatment strategies.