Systemic lipid metabolic alterations and the tumor microenvironment: A hidden driver of immune dysfunction.

Emerging evidence suggests that systemic dyslipidemias, traditionally recognized as major risk factors for cardiovascular disease, are critical modulators of immune responses. Meanwhile, cancer immunology research focuses on exploiting the immune system to more effectively target tumor cells by enhancing antitumor immunity and overcoming immune suppression within the tumor microenvironment (TME). The growing evidence connecting dyslipidemia-related diseases to tumor progression highlights lipid dysregulation as a potential driver of immune dysfunction in cancer. Elevated circulating lipids, beyond affecting local tumor metabolism, can precondition and reprogram immune cells, reshaping the TME and ultimately influencing tumor fate and cancer progression. This review summarizes how these systemic lipid alterations affect key immune populations, including CD8⁺ T cells, regulatory T cells (Tregs), natural killer cells (NKs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and dendritic cells (DCs), through mechanisms involving lipid uptake, peroxidation, and altered signaling pathways. Understanding the interplay between systemic lipid metabolism and local immune reprogramming may inform personalized strategies to improve cancer immunotherapy treatment outcomes.