Immune evasion driven by lipid metabolic reprogramming in endocrine-resistant HR+ breast cancer: antigen presentation defects and T-cell dysfunction.

Endocrine therapy has improved the prognosis of patients with hormone receptor-positive (HR+) breast cancer. However, acquired resistance remains a major cause of recurrence and progression, and the limited response of this subtype to immunotherapy highlights the need to better understand the mechanisms underlying immune escape. Recent studies indicate that, in addition to an immunosuppressive microenvironment, alterations in antigen processing and presentation may also contribute to immune escape, although systematic integration of these mechanisms remains lacking. Lipid metabolic reprogramming, as a key feature of tumor metabolic remodeling, supports tumor cell survival and adaptive evolution in endocrine-resistant HR+ breast cancer and may also regulate antitumor immune responses through multilevel mechanisms. At the tumor cell level, enhanced fatty acid oxidation, increased lipid synthesis, and altered cholesterol metabolism may affect tumor immune visibility by influencing antigen presentation-related processes, including MHC class I-associated pathways. Within the immune microenvironment, lipid accumulation may contribute to dendritic cell dysfunction and promote the polarization of tumor-associated macrophages toward immunosuppressive phenotypes, thereby impairing antigen presentation. Consequently, persistent and inefficient antigen stimulation may promote T-cell dysfunction and exhaustion. This article systematically integrates the role of lipid metabolism in antigen presentation and T-cell regulation, and proposes a dysfunctional multilevel mechanistic axis of "lipid metabolism-antigen presentation-T-cell function", providing a theoretical basis for understanding immune evasion associated with endocrine resistance and for developing combination therapeutic strategies.