化疗与免疫疗法相结合已逐渐显示出在增加 T 细胞浸润和抗肿瘤功效方面的巨大前景。然而，紫杉醇联合针对PD-1/PD-L1的免疫检查点抑制剂仅用于治疗一小部分转移性三阴性乳腺癌（TNBC），临床效果非常有限。此外，该方案不能预防紫杉醇引起的周围神经病变。因此，迫切需要一个新的靶点来增强紫杉醇的抗肿瘤活性并减轻乳腺癌化疗引起的周围神经病变。在这里，我们发现在基于紫杉醇的化疗后，Dickkopf-1 (DKK1) 表达在人类乳腺癌标本的多种亚型中上调。机制研究表明，紫杉醇通过诱导乳腺癌细胞中的EGFR信号传导来促进DKK1的表达，而DKK1的上调可以通过抑制肿瘤微环境中CD8 T细胞的浸润和活性来阻碍紫杉醇的治疗效果。此外，荷瘤小鼠的紫杉醇治疗还通过激活初级感觉背根神经节（DRG）神经元中的 EGFR 信号传导增加了 DKK1 表达，导致周围神经病变的发展，其特征是坐骨神经中的髓磷脂损伤。神经性疼痛和后爪皮肤的皮肤神经支配丧失。添加抗DKK1抗体不仅提高了紫杉醇在两种小鼠亚型乳腺癌模型中的治疗效果，而且减轻了紫杉醇诱导的周围神经病变。总而言之，我们的研究结果提供了一种具有低神经毒性的潜在化学免疫治疗策略，可以使多种亚型乳腺癌患者受益。© 2024。作者。

Chemotherapy in combination with immunotherapy has gradually shown substantial promise to increase T cell infiltration and antitumor efficacy. However, paclitaxel in combination with immune checkpoint inhibitor targeting PD-1/PD-L1 was only used to treat a small proportion of metastatic triple-negative breast cancer (TNBC), and the clinical outcomes was very limited. In addition, this regimen cannot prevent paclitaxel-induced peripheral neuropathy. Therefore, there was an urgent need for a novel target to enhance the antitumor activity of paclitaxel and alleviate chemotherapy-induced peripheral neuropathy in breast cancer. Here, we found that Dickkopf-1 (DKK1) expression was upregulated in multiply subtypes of human breast cancer specimens after paclitaxel-based chemotherapy. Mechanistic studies revealed that paclitaxel promoted DKK1 expression by inducing EGFR signaling in breast cancer cells, and the upregulation of DKK1 could hinder the therapeutic efficacy of paclitaxel by suppressing the infiltration and activity of CD8+ T cells in tumor microenvironment. Moreover, paclitaxel treatment in tumor-bearing mice also increased DKK1 expression through the activation of EGFR signaling in the primary sensory dorsal root ganglion (DRG) neurons, leading to the development of peripheral neuropathy, which is charactered by myelin damage in the sciatic nerve, neuropathic pain, and loss of cutaneous innervation in hindpaw skin. The addition of an anti-DKK1 antibody not only improved therapeutic efficacy of paclitaxel in two murine subtype models of breast cancer but also alleviated paclitaxel-induced peripheral neuropathy. Taken together, our findings providing a potential chemoimmunotherapy strategy with low neurotoxicity that can benefit multiple subtypes of breast cancer patients.© 2024. The Author(s).