{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T22:19:26Z","timestamp":1793225966051,"version":"4.5.0"},"reference-count":59,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"unspecified","delay-in-days":27,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Fundamental Research Funds for the Zhejiang Provincial Universities","award":["226-2024-00181"],"award-info":[{"award-number":["226-2024-00181"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81930079"],"award-info":[{"award-number":["81930079"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82302901"],"award-info":[{"award-number":["82302901"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82403364"],"award-info":[{"award-number":["82403364"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U22A20321"],"award-info":[{"award-number":["U22A20321"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Zhejiang Clinovation Pride","award":["CXTD202501018"],"award-info":[{"award-number":["CXTD202501018"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,7,7]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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 \u03b3\u03b4 T cells, remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed single-cell RNA sequencing and spatial profiling of paired specimens from patients with BC. Integrated multi-omics analyses, immunofluorescence staining, human \u03b3\u03b4 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 \u03b3\u03b4 T-cell activation and signaling. Clinical correlations were assessed using our cohort and patient datasets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified a previously unrecognized population of NKG2A\n                      <jats:sup>+<\/jats:sup>\n                      \u03b3\u03b4 T cells with predominant V\u03b42 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 \u03b3\u03b4 T cells and upregulating NKG2A expression. NKG2A\n                      <jats:sup>+<\/jats:sup>\n                      \u03b3\u03b4 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 \u03b3\u03b4 T cell-mediated antitumor responses. Importantly, LTB4-programmed \u03b3\u03b4 T cells displayed superior killing capacity using in vitro and in vivo assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings redefine PA as an active immunological niche that programs \u03b3\u03b4 T-cell immunity through adipocyte-derived LTB4 signaling. Our study identifies NKG2A\n                      <jats:sup>+<\/jats:sup>\n                      \u03b3\u03b4 T cells as cytotoxic sentinels at the adipose-tumor interface during early tumor development, providing a rationale for leveraging LTB4-mediated \u03b3\u03b4 T-cell programming in translational cancer immunotherapy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-015147","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T12:25:20Z","timestamp":1785241520000},"page":"e015147","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Adipocyte-derived LTB4 programs human NKG2A\n                    <sup>+<\/sup>\n                    \u03b3\u03b4 T cells as cytotoxic sentinels at the adipose-tumor interface in breast cancer"],"prefix":"10.1136","volume":"14","author":[{"given":"Xiaoxiao","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Breast Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"},{"name":"Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dang","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"},{"name":"Department of Radiation Oncology, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"},{"name":"Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangsang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouyu","family":"Ke","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, The Second Affiliated Hospital Zhejiang University School of 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