贝塔肾上腺素受体阻滞剂已经与三阴性乳腺癌（TNBC）患者的癌症生存率改善相关，但这些效应的机制仍不清楚。在临床流行病学分析中，我们发现β受体阻滞剂使用与蒽环类化疗剂的应用有关，可以保护免受TNBC的进展，疾病复发和死亡的影响。我们在TNBC的异种移植小鼠模型中重现了贝塔阻滞对蒽环类药物疗效的影响。在TNBC的转移性4T1.2和MDA-MB-231小鼠模型中，贝塔阻滞通过减少转移发展来提高蒽环类药物多柔比星的疗效。我们发现，在没有贝塔阻滞的情况下，单独使用蒽环类化疗剂会通过诱导瘤细胞产生神经生长因子（NGF）来增加乳腺肿瘤的交感神经纤维活性和去甲肾上腺素浓度。此外，使用临床样本和临床试验模型，我们发现蒽环类化疗剂可以上调β2肾上腺素能受体的表达并放大肿瘤细胞中的受体信号转导。在TNBC的异种移植小鼠模型中，使用神经毒素6-羟基多巴胺或基因缺失NGF或β2 肾上腺素受体可以通过减少转移来增强蒽环类化疗剂的治疗效果。这些发现揭示了蒽环类化疗剂的神经调控效应，从而削弱其潜在的治疗影响，但这可以通过在肿瘤微环境中抑制β2 肾上腺素能信号传导来克服。将贝塔阻滞剂与蒽环类化疗剂合并使用，代表着一种增强TNBC临床治疗的潜在治疗策略。

Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated β2-adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or β2-adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting β2-adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive β2-adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.