肿瘤相关巨噬细胞（TAM）因其促肿瘤功能而成为主要治疗靶点，但巨噬细胞靶向疗法的不同功效凸显了我们对巨噬细胞在肿瘤微环境（TME）中如何调节的不完全理解。生物钟是巨噬细胞功能的关键调节因子，但 TME 如何影响巨噬细胞的昼夜节律仍不清楚。在这里，我们证明与 TME 相关的条件（例如极化刺激、酸性 pH 值和乳酸）可以改变巨噬细胞的昼夜节律。虽然据报道环 AMP (cAMP) 在巨噬细胞对酸性 pH 的反应中发挥作用，但我们的结果表明 pH 驱动的昼夜节律变化不仅仅由 cAMP 信号传导介导。值得注意的是，时钟相关距离分析揭示了 TAM 的昼夜节律紊乱。我们的数据表明，TAM 人群水平内昼夜节律的异质性可能是这种昼夜节律紊乱的原因。最后，我们报告巨噬细胞的昼夜节律调节可抑制小鼠胰腺癌模型中的肿瘤生长。我们的工作展示了一种新机制，TME 通过调节昼夜节律来影响巨噬细胞生物学。© 2024。作者。

Tumor-associated macrophages (TAMs) are prime therapeutic targets due to their pro-tumorigenic functions, but varying efficacy of macrophage-targeting therapies highlights our incomplete understanding of how macrophages are regulated within the tumor microenvironment (TME). The circadian clock is a key regulator of macrophage function, but how circadian rhythms of macrophages are influenced by the TME remains unknown. Here, we show that conditions associated with the TME such as polarizing stimuli, acidic pH, and lactate can alter circadian rhythms in macrophages. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate pH-driven changes in circadian rhythms are not mediated solely by cAMP signaling. Remarkably, circadian disorder of TAMs was revealed by clock correlation distance analysis. Our data suggest that heterogeneity in circadian rhythms within the TAM population level may underlie this circadian disorder. Finally, we report that circadian regulation of macrophages suppresses tumor growth in a murine model of pancreatic cancer. Our work demonstrates a novel mechanism by which the TME influences macrophage biology through modulation of circadian rhythms.© 2024. The Author(s).