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

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 NKG2A expression. NKG2A+γδ T cells were preferentially enriched in ductal carcinoma in situ and early-stage BC. These cells were also associated with favorable clinical outcomes across multiple adipose-enriched tumors. Assays using human specimens confirmed that LTB4 potentiated γδ T cell-mediated antitumor responses. Importantly, LTB4-programmed γδ T cells displayed superior killing capacity using in vitro and in vivo assays.

CONCLUSIONS

These findings redefine PA as an active immunological niche that programs γδ T-cell immunity through adipocyte-derived LTB4 signaling. Our study identifies NKG2A+γδ T cells as cytotoxic sentinels at the adipose-tumor interface during early tumor development, providing a rationale for leveraging LTB4-mediated γδ T-cell programming in translational cancer immunotherapy.