As the most frequent genetic alteration in cancer, more than half of human cancers have p53 mutations that cause transcriptional inactivation. However, how p53 modulates the immune landscape to create a niche for immune escape remains elusive. We found that cancer stem cells (CSCs) established an interleukin-34 (IL-34)-orchestrated niche to promote tumorigenesis in p53-inactivated liver cancer. Mechanistically, we discovered that Il34 is a gene transcriptionally repressed by p53, and p53 loss resulted in IL-34 secretion by CSCs. IL-34 induced CD36-mediated elevations in fatty acid oxidative metabolism to drive M2-like polarization of foam-like tumor-associated macrophages (TAMs). These IL-34-orchestrated TAMs suppressed CD8+ T cell-mediated antitumor immunity to promote immune escape. Blockade of the IL-34-CD36 axis elicited antitumor immunity and synergized with anti-PD-1 immunotherapy, leading to a complete response. Our findings reveal the underlying mechanism of p53 modulation of the tumor immune microenvironment and provide a potential target for immunotherapy of cancer with p53 inactivation.

中文翻译：

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白细胞介素 34 协调的肿瘤相关巨噬细胞重编程是 p53 失活驱动的肿瘤免疫逃逸所必需的


作为癌症中最常见的基因改变，超过一半的人类癌症具有导致转录失活的 p53 突变。然而，p53 如何调节免疫景观以创造免疫逃逸的生态位仍然难以捉摸。我们发现癌症干细胞 （CSCs） 建立了白细胞介素 34 （IL-34） 编排的生态位，以促进 p53 灭活肝癌的肿瘤发生。从机制上讲，我们发现 Il34 是一个被 p53 转录抑制的基因，p53 缺失导致 CSCs 分泌 IL-34。IL-34 诱导 CD36 介导的脂肪酸氧化代谢升高，以驱动泡沫样肿瘤相关巨噬细胞 （TAM） 的 M2 样极化。这些 IL-34 编排的 TAMs 抑制 CD8+ T 细胞介导的抗肿瘤免疫，促进免疫逃逸。阻断 IL-34-CD36 轴引发抗肿瘤免疫，并与抗 PD-1 免疫疗法协同作用，导致完全反应。我们的研究结果揭示了 p53 调节肿瘤免疫微环境的潜在机制，并为 p53 失活癌症的免疫治疗提供了潜在的靶点。