Wnt5a is the prototypical activator of the non-canonical Wnt pathways, and its overexpression has been implicated in the progression of several tumor types by promoting cell motility, invasion, EMT, and metastasis. Recent evidences have revealed a novel role of Wnt5a in the phosphorylation of the NF-κB subunit p65 and the activation of the NF-κB pathway in cancer cells. In this article, we review the molecular mechanisms and mediators defining a Wnt5a/NF-κB signaling pathway and propose that the aberrant expression of Wnt5a in some tumors drives a Wnt5a/NF-κB/IL-6/STAT3 positive feedback loop that amplifies the effects of Wnt5a. The evidences discussed here suggest that Wnt5a has a double effect on the tumor microenvironment. First, it activates an autocrine ROR1/Akt/p65 pathway that promotes inflammation and chemotaxis of immune cells. Then, Wnt5a activates a TLR/MyD88/p50 pathway exclusively in myelomonocytic cells promoting the synthesis of the anti-inflammatory cytokine IL-10 and a tolerogenic phenotype. As a result of these mechanisms, Wnt5a plays a negative role on immune cell function that contributes to an immunosuppressive tumor microenvironment and would contribute to resistance to immunotherapy. Finally, we summarized the development of different strategies targeting either Wnt5a or the Wnt5a receptor ROR1 that can be helpful for cancer therapy by contributing to generate a more immunostimulatory tumor microenvironment.

中文翻译：

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Wnt5a 在促进促炎和免疫抑制肿瘤微环境中的新作用

Wnt5a 是非经典 Wnt 通路的原型激活剂，它的过表达通过促进细胞运动、侵袭、EMT 和转移与几种肿瘤类型的进展有关。最近的证据揭示了 Wnt5a 在 NF-κB 亚基 p65 的磷酸化和癌细胞中 NF-κB 通路的激活中的新作用。在本文中，我们回顾了定义 Wnt5a/NF-κB 信号通路的分子机制和介质，并提出 Wnt5a 在某些肿瘤中的异常表达驱动了 Wnt5a/NF-κB/IL-6/STAT3 正反馈回路，从而放大了Wnt5a 的影响。这里讨论的证据表明 Wnt5a 对肿瘤微环境具有双重作用。首先，它激活自分泌 ROR1/Akt/p65 通路，促进免疫细胞的炎症和趋化性。然后，Wnt5a 仅在骨髓单核细胞中激活 TLR/MyD88/p50 通路，促进抗炎细胞因子 IL-10 的合成和致耐受表型。由于这些机制，Wnt5a 对免疫细胞功能起着负面作用，这有助于免疫抑制性肿瘤微环境，并有助于对免疫疗法的抵抗。最后，我们总结了针对 Wnt5a 或 Wnt5a 受体 ROR1 的不同策略的发展，这些策略有助于产生更具免疫刺激性的肿瘤微环境，从而有助于癌症治疗。Wnt5a 对免疫细胞功能起负面作用，免疫细胞功能有助于形成免疫抑制性肿瘤微环境，并有助于对免疫疗法产生抗性。最后，我们总结了针对 Wnt5a 或 Wnt5a 受体 ROR1 的不同策略的发展，这些策略有助于产生更具免疫刺激性的肿瘤微环境，从而有助于癌症治疗。Wnt5a 对免疫细胞功能起负面作用，免疫细胞功能有助于形成免疫抑制性肿瘤微环境，并有助于对免疫疗法产生抗性。最后，我们总结了针对 Wnt5a 或 Wnt5a 受体 ROR1 的不同策略的发展，这些策略有助于产生更具免疫刺激性的肿瘤微环境，从而有助于癌症治疗。