因此,该研究结果表明,肿瘤相关巨噬细胞通过非经典吞噬引起不依赖于Rag鸟苷酸三磷酸酶的mTORC1信号传导,可控制肿瘤相关巨噬细胞与癌细胞之间的竞争,这定义了一种新的先天免疫肿瘤抑制途径,可以作为乳腺癌治疗的新靶点,也为正常蛋白质饮食战胜乳腺癌奠定了基础,故有必要进一步开展临床研究进行验证。 Nature. 2023 Jun 28. IF: 69.504 Reprogramming tumour-associated macrophages to outcompete cancer cells. Xian Zhang, Shun Li, Isha Malik, Mytrang H. Do, Liangliang Ji, Chun Chou, Wei Shi, Kristelle J. Capistrano, Jing Zhang, Ting-Wei Hsu, Briana G. Nixon, Ke Xu, Xinxin Wang, Andrea Ballabio, Laura S. Schmidt, W. Marston Linehan, Ming O. Li. Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA; Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; National Cancer Institute, Bethesda, MD, USA; Frederick National Laboratory for Cancer Research, Frederick, MD, USA; Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Federico II University, Naples, Italy. In metazoan organisms, cell competition acts as a quality control mechanism to eliminate unfit cells in favour of their more robust neighbours. This mechanism has the potential to be maladapted, promoting the selection of aggressive cancer cells. Tumours are metabolically active and are populated by stroma cells, but how environmental factors affect cancer cell competition remains largely unknown. Here we show that tumour-associated macrophages (TAMs) can be dietarily or genetically reprogrammed to outcompete MYC-overexpressing cancer cells. In a mouse model of breast cancer, MYC overexpression resulted in an mTORC1-dependent 'winner' cancer cell state. A low-protein diet inhibited mTORC1 signalling in cancer cells and reduced tumour growth, owing unexpectedly to activation of the transcription factors TFEB and TFE3 and mTORC1 in TAMs. Diet-derived cytosolic amino acids are sensed by Rag GTPases through the GTPase-activating proteins GATOR1 and FLCN to control Rag GTPase effectors including TFEB and TFE3. Depletion of GATOR1 in TAMs suppressed the activation of TFEB, TFE3 and mTORC1 under the low-protein diet condition, causing accelerated tumour growth; conversely, depletion of FLCN or Rag GTPases in TAMs activated TFEB, TFE3 and mTORC1 under the normal protein diet condition, causing decelerated tumour growth. Furthermore, mTORC1 hyperactivation in TAMs and cancer cells and their competitive fitness were dependent on the endolysosomal engulfment regulator PIKfyve. Thus, noncanonical engulfment-mediated Rag GTPase-independent mTORC1 signalling in TAMs controls competition between TAMs and cancer cells, which defines a novel innate immune tumour suppression pathway that could be targeted for cancer therapy. PMID: 37380769 DOI: 10.1038/s41586-023-06256-5