Journal for immunotherapy of cancer · 2026
Adipocyte-derived LTB4 programs human NKG2A+ γδ T cells as cytotoxic sentinels at the adipose-tumor interface in breast cancer.
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Hu Xiaoxiao, Wu Dang, Jia Fang, Zhu Sangsang, Ke Shouyu, Chen Di, Zhao Jing, Li Lili, Zhang Yi, Wang Zhen, Jin Xiaoyan, Zhu Wangyu, Huang Fengbo, Chen Hailang, Xing Ping, Ding Jinhua, Meng Liwei, Ding Yunfeng, Wang Yongpan, Xu Jing, Ren Guohong, Chen Wuzhen, Shao Xuan, Ni Chao, Yu Xiuyan, Pang Liwei, Zhang Leyi, Pan Jun, Pan Weiwei, Xu Ningning, Yu Zhuohang, Qiu Fuming, Yan Jun, Huang Jian
Аннотация
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.
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.