三阴性乳腺癌 (TNBC) 由于其复杂的性质和需要更有效的治疗而带来了独特的挑战。最近的研究显示，紫杉醇 (PTX) 与程序性细胞死亡蛋白 1 (PD-1) 阻断联合治疗 TNBC 取得了令人鼓舞的结果，尽管改善结果背后的确切机制尚不清楚。我们采用了一种综合方法，分析空间转录组学和单一来自 TNBC 患者的细胞 RNA 测序数据，以了解为什么 PTX 和 PD-1 阻断联合治疗在 TNBC 患者中显示出更好的反应。我们重点关注 Toll 样受体 4 (TLR4)（PTX 的一种受体）及其在调节肿瘤微环境中肿瘤相关巨噬细胞 (TAM) 交叉呈递信号通路中的作用。利用从患者数据中获得的见解，我们使用免疫抑制性骨髓源性巨噬细胞 (iBMDM) 进行了体外实验，以验证 PTX 是否可以增强交叉呈递和吞噬活性。随后，我们将研究扩展到 TNBC 体内小鼠模型，以确定 PTX 对 TAM 交叉呈递能力的影响及其对 CD8 T 细胞介导的免疫反应的下游影响。 TNBC 患者的数据分析表明，激活TLR4 和交叉呈递信号通路的变化对于 PTX 的抗肿瘤功效至关重要。体外研究表明 PTX 治疗增强了 iBMDM 的交叉呈递能力。体内实验表明，PTX 激活 TAM 中 TLR4 依赖性交叉呈递，改善 CD8 T 细胞介导的抗肿瘤反应。当与 PD-1 阻断剂联合使用时，PTX 可以促进抗肿瘤免疫，这表明存在互补的相互作用。这项研究揭示了 PTX 如何增强 PD-1 抑制剂治疗 TNBC 的有效性。我们发现 PTX 激活 TAM 中的 TLR4 信号传导。这种激活增强了它们呈递抗原的能力，从而增强 CD8 T 细胞的抗肿瘤反应。这些发现不仅揭示了 PTX 在 TNBC 中的免疫调节作用，还强调了在免疫治疗方法中针对 TAM 抗原呈递能力的潜力。© 作者（或其雇主）2024。CC BY 允许重复使用-NC。不得商业再利用。请参阅权利和权限。由英国医学杂志出版。

Triple-negative breast cancer (TNBC) poses unique challenges due to its complex nature and the need for more effective treatments. Recent studies showed encouraging outcomes from combining paclitaxel (PTX) with programmed cell death protein-1 (PD-1) blockade in treating TNBC, although the exact mechanisms behind the improved results are unclear.We employed an integrated approach, analyzing spatial transcriptomics and single-cell RNA sequencing data from TNBC patients to understand why the combination of PTX and PD-1 blockade showed better response in TNBC patients. We focused on toll-like receptor 4 (TLR4), a receptor of PTX, and its role in modulating the cross-presentation signaling pathways in tumor-associated macrophages (TAMs) within the tumor microenvironment. Leveraging insights obtained from patient-derived data, we conducted in vitro experiments using immunosuppressive bone marrow-derived macrophages (iBMDMs) to validate if PTX could augment the cross-presentation and phagocytosis activities. Subsequently, we extended our study to an in vivo murine model of TNBC to ascertain the effects of PTX on the cross-presentation capabilities of TAMs and its downstream impact on CD8+ T cell-mediated immune responses.Data analysis from TNBC patients revealed that the activation of TLR4 and cross-presentation signaling pathways are crucial for the antitumor efficacy of PTX. In vitro studies showed that PTX treatment enhances the cross-presentation ability of iBMDMs. In vivo experiments demonstrated that PTX activates TLR4-dependent cross-presentation in TAMs, improving CD8+ T cell-mediated antitumor responses. The efficacy of PTX in promoting antitumor immunity was elicited when combined with PD-1 blockade, suggesting a complementary interaction.This study reveals how PTX boosts the effectiveness of PD-1 inhibitors in treating TNBC. We found that PTX activates TLR4 signaling in TAMs. This activation enhances their ability to present antigens, thereby boosting CD8+ T cell antitumor responses. These findings not only shed light on PTX's immunomodulatory role in TNBC but also underscore the potential of targeting TAMs' antigen presentation capabilities in immunotherapy approaches.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.