由于肿瘤微环境（TME）的异质性和免疫抑制性，当前手术和化疗对三阴性乳腺癌（TNBC）的疗效有限。肿瘤相关巨噬细胞 (TAM) 被认为是 M2 肿瘤促进表型，在免疫抑制性 TME 的发展中至关重要。靶向TAM重编程是抗肿瘤治疗中一种很有前途的策略，因为重编程技术除了消除TAM的肿瘤支持作用之外，还提供了主动增强TAM抗肿瘤免疫活性的机会，这在临床上很少应用于TNBC。然而，如何高效地驱动 M2 巨噬细胞重编程为 M1 仍然是一个挑战，而且 M2 巨噬细胞极化为 M1 的分子机制知之甚少。在这里，我们鉴定了一种新的免疫调节分子PepO，它作为免疫调节分子控制促进肿瘤的M2细胞向抑制肿瘤的M1细胞的转化，并具有有效的抗肿瘤特性。在本研究中，我们鉴定了一种新的免疫调节分子PepO作为一种无害的免疫调节分子，能够有效调控促肿瘤M2细胞向抑癌M1细胞的转化。 PepO引发的M2巨噬细胞降低了Arg-1、Tgfb、Vegfa和IL-10等肿瘤支持分子的表达，并增加了iNOS、Cxcl9、Cxcl10、TNF-α和IL-6的表达，从而抑制TNBC生长。此外，PepO增强巨噬细胞与细胞杀伤、吞噬和一氧化氮生物合成过程相关的功能，从而在体内和体外抑制肿瘤的发展。从机制上讲，PepO 通过 TLR4 激活 PI3K-AKT-mTOR 通路将 TAM 重编程为 M1，并通过 TLR2 抑制 JAK2-STAT3 通路来抑制 M2 的功能。 PI3K 抑制剂 LY294002 消除了 PepO 将 M2 巨噬细胞转变为 M1 以及抑制体内 TNBC 生长的作用。当TLR2或TLR4缺陷时，PepO无法控制M2巨噬细胞重编程为M1巨噬细胞并抑制TNBC。此外，PepO 增强了阿霉素的抗肿瘤活性，并且组合对 TNBC 抑制发挥协同作用。我们的研究发现了一种可能的基于巨噬细胞的 TNBC 免疫治疗方法，并提出了一种名为 PepO 的新型抗癌免疫调节分子。© 2023。作者。

The efficacy of current surgery and chemotherapy for triple negative breast cancer (TNBC) is limited due to heterogenous and immunosuppressive tumor microenvironment (TME). Tumor associated macrophages (TAMs), which are regarded as an M2 tumor-promoting phenotype, are crucial in the development of the immunosuppressive TME. Targeting TAM reprograming is a promising strategy in anti-tumor therapy since reprogramming techniques provide the opportunity to actively enhance the antitumor immunological activity of TAM in addition to eliminating their tumor-supportive roles, which is rarely applied in TNBC clinically. However, how to drive M2 macrophages reprogramming into M1 with high potency remains a challenge and the molecular mechanisms how M2 macrophages polarized into M1 are poorly understood. Here, we identified a new immunoregulatory molecular PepO that was served as an immunoregulatory molecule governed the transformation of tumor-promoting M2 to tumor-inhibitory M1 cells and represented an effective anti-tumor property.At the present study, we identified a new immunoregulatory molecular PepO, as a harmless immunoregulatory molecule, governed the transformation of tumor-promoting M2 to tumor-inhibitory M1 cells efficiently. PepO-primed M2 macrophages decreased the expression of tumor-supportive molecules like Arg-1, Tgfb, Vegfa and IL-10, and increased the expression of iNOS, Cxcl9, Cxcl10, TNF-α and IL-6 to inhibit TNBC growth. Moreover, PepO enhanced the functions of macrophages related to cell killing, phagocytosis and nitric oxide biosynthetic process, thereby inhibiting the development of tumors in vivo and in vitro. Mechanistically, PepO reprogramed TAMs toward M1 by activating PI3K-AKT-mTOR pathway via TLR4 and suppressed the function of M2 by inhibiting JAK2-STAT3 pathway via TLR2. The PI3K inhibitor LY294002 abrogated the role of PepO in switching M2 macrophages into M1 and in inhibiting TNBC growth in vivo. And PepO failed to govern the M2 macrophages to reprogram into M1 macrophages and inhibit TNBC when TLR2 or TLR4 was deficient. Moreover, PepO enhanced the antitumor activity of doxorubicin and the combination exerted a synergistic effect on TNBC suppression.Our research identified a possible macrophage-based TNBC immunotherapeutic approach and suggested a novel anticancer immunoregulatory molecular called PepO.© 2023. The Author(s).