近日，德国维尔茨堡大学教授Angela Riedel及小组的最新研究提出了肿瘤引流淋巴结中TLR4依赖的成纤维细胞单核细胞轴有助于三阴性乳腺癌的转移。相关论文发表在2025年9月15日出版的《免疫学》杂志上。

该课题组人员研究了三阴性乳腺癌（TNBC）中TDLNs内的细胞网络是如何重组的。该研究团队发现，在转移性TNBC单母肿瘤的TDLNs中，程序性死亡配体1高（PD-L1^hi）单核细胞的频率增加。纤维母细胞网状细胞（FRC）亚型升高趋化因子CCL2和CCL7的表达，支持CCR2⁺单核细胞的归巢。这些单核细胞通过PD-L1和诱导型一氧化氮合酶（iNOS）在体外抑制T细胞。空间转录组学显示在血管化区和T细胞区有免疫抑制的FRC-单核细胞壁龛。肿瘤相关Toll样受体（TLR） 4配体通过FRCs诱导CCL2和CCL7表达，促进单核细胞募集。局部TLR4抑制联合抗程序性细胞死亡蛋白1 （αPD-1）治疗可减少单核细胞归巢，增强T细胞功能，最终减轻肺转移。单核细胞在人类TNBC TDLNs中积累，有证据表明FRC-单核细胞轴和TLR4配体特征可预测TNBC患者的不良生存结果。因此，转移性TNBC可以重新编程淋巴结（LNs），以促进PD-L1介导的免疫逃避和转移。

据悉，肿瘤引流淋巴结（TDLNs）是抗肿瘤免疫启动和转移的部位。

附：英文原文

Title: A TLR4-dependent fibroblast-monocyte axis in tumor-draining lymph nodes contributes to metastasis in triple-negative breast cancer

Author: Greta Mattavelli, Moutaz Helal, Ana Cetkovic, Maximilian J. Krmer, Saskia-Laureen Herbert, Kilian Mielert, Tanja Schlai, Anna Frank, Emily Riemer, Mara John, Josefina del Pilar, Martinez Vasquez, Laura Kindl, Jonathan J. Swietlik, Benedikt O. Gansen, Marion Krafft, Emilia Stanojkovska, Hanna Fischer, Ute-Susann Albert, Jonas Bauer, Murilo Delgobo, Arpa Aintablian, Haisam Alattar, Manfred B. Lutz, Felix Meissner, Thordur Oskarsson, Leo Rasche, Gustavo Ramos, Andreas Rosenwald, Achim Wckel, Angela Riedel

Issue&Volume: 2025-09-15

Abstract: Tumor-draining lymph nodes (TDLNs) are sites of anti-tumor immune priming as well as metastases. Here, we examined how the cellular networks within TDLNs are reorganized in triple-negative breast cancer (TNBC). We found that the frequencies of programmed death ligand 1 high (PD-L1hi) monocytes increased in TDLNs of metastatic TNBC mouse tumors. Fibroblastic reticular cell (FRC) subtypes heightened the expression of the chemokines CCL2 and CCL7, supporting the homing of CCR2+ monocytes. These monocytes suppressed T cells in vitro via PD-L1 and inducible nitric oxide synthase (iNOS). Spatial transcriptomics revealed immunosuppressive FRC-monocyte niches in vascularized and T cell areas. Tumor-associated Toll-like receptor (TLR) 4 ligands induced CCL2 and CCL7 expression by FRCs to promote monocyte recruitment. Localized TLR4 inhibition in combination with anti-programmed cell death protein 1 (αPD-1) therapy reduced monocyte homing and boosted T cell function, ultimately attenuating lung metastases. Monocytes accumulate in human TNBC TDLNs, with evidence of a FRC-monocyte axis, and a TLR4 ligand signature is predictive of poor survival outcomes in TNBC patients. Thus, metastatic TNBC can reprogram lymph nodes (LNs) to facilitate PD-L1-mediated immune evasion and metastasis.

DOI: 10.1016/j.immuni.2025.08.015

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00378-4