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利基仍然难以捉摸。我们发现癌症干细胞 (CSC) 建立了白细胞介素 34 (IL-34) 协调的生态位，以促进 p53 失活的肝癌中的肿瘤发生。从机制上讲，我们发现 Il34 是 p53 转录抑制的基因，p53 缺失导致 CSC 分泌 IL-34。 IL-34 诱导 CD36 介导的脂肪酸氧化代谢升高，从而驱动泡沫样肿瘤相关巨噬细胞 (TAM) 的 M2 样极化。这些 IL-34 协调的 TAM 抑制 CD8 T 细胞介导的抗肿瘤免疫，从而促进免疫逃逸。阻断 IL-34-CD36 轴可引发抗肿瘤免疫，并与抗 PD-1 免疫疗法协同作用，从而实现完全缓解。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 失活的癌症免疫治疗提供了潜在靶点。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.