Adipocyte-derived LTB4 programs human NKG2A(+) γδ T cells as cytotoxic sentinels at the adipose-tumor interface in breast cancer

作者：Hu X, Wu D, Jia F, Zhu S, Ke S, Chen D, Zhao J, Li L, Zhang Y, Wang Z, Jin X, Zhu W, Huang F, Chen H, Xing P, Ding J, Meng L, Ding Y, Wang Y, Xu J, Ren G, Chen W, Shao X, Ni C, Yu X, Pang L, Zhang L, Pan J, Pan W, Xu N, Yu Z, Qiu F, Yan J, Huang J · 发表于：Journal for immunotherapy of cancer · 年份：2026 · DOI：10.1136/jitc-2026-015147 · 被引用次数：59 · 研究领域：Breast Neoplasms、Leukotriene B4、Adipocytes、Adipose Tissue、Receptors, Antigen, T-Cell, gamma-delta、Humans、Female、Tumor Microenvironment、Animals、Mice

BACKGROUND: The peritumoral microenvironment has emerged as a key role in affecting tumor invasion and immunotherapy responses. In adipose-enriched tumors, such as breast cancer (BC), peritumoral adipose tissue (PA) harbors unconventional immune populations, yet its immunological functions remain poorly understood. In particular, how adipocyte regulate innate-like lymphocytes, such as γδ T cells, remains unclear. METHODS: We performed single-cell RNA sequencing and spatial profiling of paired specimens from patients with BC. Integrated multi-omics analyses, immunofluorescence staining, human γδ T-cell expansion assays, functional assays, and in vivo models were used to define the immune cell states and evaluate the impact of lipid mediator leukotriene B4 (LTB4) on γδ T-cell activation and signaling. Clinical correlations were assessed using our cohort and patient datasets. RESULTS: We identified a previously unrecognized population of NKG2A+γδ T cells with predominant Vδ2 usage that preferentially accumulated in PA, particularly at the adipose-tumor interface. Multi-omics analyses revealed that they exhibited potent cytotoxic activity and extensive interactions with dendritic cells, coordinating a local immune surveillance network. Mechanistically, peritumoral adipocytes showed enhanced activation of the 5-lipoxygenase pathway and secreted the lipid mediator LTB4, which selectively combined to LTB4 receptors, thereby activating STAT1 signaling in γδ T cells and upregulating...