在三阴性乳腺癌（TNBC）中，肿瘤免疫微环境（TIME）是一个高度异质的生态系统，在肿瘤发生和进展中发挥着不可或缺的作用。癌症相关成纤维细胞（CAF）和癌症相关脂肪细胞（CAA）是TNBC TIME中的主要基质成分。 CAF 介导促水肿反应，这是免疫抑制微环境促进肿瘤生长的主要驱动力。此外，CAAs是一种肿瘤培养的脂肪细胞，参与与乳腺癌的串扰，能够分泌多种细胞因子、脂肪因子和趋化因子，特别是C-C基序趋化因子配体2（CCL2），导致癌细胞表型和功能的变化。因此，本文研究如何通过CAA及时调节CAF和CCL2的分泌来治疗肿瘤。我们的研究小组之前发现，大黄酸 (Rhe) 已被确定可有效对抗 CAF，而橙皮苷 (Hes) 则可有效减少 CAA 分泌的 CCL2。受上述启发，我们利用乳液溶剂扩散法开发了独特的基于 PLGA 的负载 Rhe 和 Hes 的纳米颗粒（RH-NP）。 RH-NP 颗粒的平均尺寸为 114.1 ± 0.98 nm。 RH-NP 有效减少 CAF 并抑制 CAA 分泌 CCL2，促进细胞毒性 T 细胞浸润增加并减少肿瘤内免疫抑制细胞的存在。这种创新、安全、低毒、高效的抗肿瘤策略在 TNBC 治疗中具有广阔的前景。版权所有 © 2024 Elsevier B.V. 保留所有权利。

In triple-negative breast cancer (TNBC), the tumor immune microenvironment (TIME) is a highly heterogeneous ecosystem that exerts indispensable roles in tumorigenesis and tumor progression. Cancer-associated fibroblasts (CAFs) and cancer-associated adipocytes (CAAs) are the main matrix components in the TIME of TNBC. CAFs mediate the edesmoplastic response, which is a major driver of the immunosuppressive microenvironment to promote tumor growth. In addition, CAAs, a type of tumor-educated adipocyte, participate in crosstalk with breast cancer and are capable of secreting various cytokines, adipokines and chemokines, especially C-C Motif Chemokine Ligand 2 (CCL2), resulting in changes of cancer cell phenotype and function. Therefore, how to treat tumors by regulating the CAFs and the secretion of CCL2 by CAAs in TIME is investigated here. Our research group previously found that rhein (Rhe) has been identified as effective against CAFs, while hesperidin (Hes) could effectively diminish CCL2 secretion by CAAs. Inspired by the above, we developed unique PLGA-based nanoparticles loaded with Rhe and Hes (RH-NP) using the emulsion solvent diffusion method. The RH-NP particles have an average size of 114.1 ± 0.98 nm. RH-NP effectively reduces CAFs and inhibits CCL2 secretion by CAAs, promoting increased infiltration of cytotoxic T cells and reducing immunosuppressive cell presence within tumors. This innovative, safe, low-toxic, and highly effective anti-tumor strategy could be prospective in TNBC treatment.Copyright © 2024 Elsevier B.V. All rights reserved.