Wang Bixin, Cao Xu, Garcia-Mansfield Krystine, Zhou Jingkai, Manousopoulou Antigoni, Pirrotte Patrick, Wang Yingyu, Wang Leo D, Feng Mingye
Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Cancer and Cell Biology Division, Translational Genomics Institute, Phoenix, AZ 85004, USA.
Cancers (Basel). 2024 Dec 19;16(24):4238. doi: 10.3390/cancers16244238.
: Macrophage-mediated cancer cell phagocytosis has demonstrated considerable therapeutic potential. While the initiation of phagocytosis, facilitated by interactions between cancer cell surface signals and macrophage receptors, has been characterized, the mechanisms underlying its sustentation and attenuation post-initiation remain poorly understood. : Through comprehensive phosphoproteomic profiling, we interrogated the temporal evolution of the phosphorylation profiles within macrophages during cancer cell phagocytosis. : Our findings reveal that activation of the mTOR pathway occurs following the initiation of phagocytosis and is crucial in sustaining phagocytosis of cancer cells. mTOR inhibition impaired the phagocytic capacity, but not affinity, of the macrophages toward the cancer cells by delaying phagosome maturation and impeding the transition between non-phagocytic and phagocytic states of macrophages. : Our findings delineate the intricate landscape of macrophage phagocytosis and highlight the pivotal role of the mTOR pathway in mediating this process, offering valuable mechanistic insights for therapeutic interventions.
巨噬细胞介导的癌细胞吞噬作用已显示出巨大的治疗潜力。虽然由癌细胞表面信号与巨噬细胞受体之间的相互作用促进的吞噬作用起始已得到表征，但其起始后维持和减弱的潜在机制仍知之甚少。通过全面的磷酸化蛋白质组学分析，我们研究了癌细胞吞噬过程中巨噬细胞内磷酸化谱的时间演变。我们的研究结果表明，mTOR通路在吞噬作用起始后被激活，并且在维持癌细胞的吞噬作用中至关重要。mTOR抑制通过延迟吞噬体成熟和阻碍巨噬细胞非吞噬状态与吞噬状态之间的转变，损害了巨噬细胞对癌细胞的吞噬能力，但不影响其亲和力。我们的研究结果描绘了巨噬细胞吞噬作用的复杂图景，并突出了mTOR通路在介导这一过程中的关键作用，为治疗干预提供了有价值的机制见解。
