在之前的研究中，我们报道了在乳腺癌早期部位的肿瘤相关巨噬细胞（TAM）的ATP产生速率降低以及对氧化磷酸化的依赖程度增加。由于这些变化可能是由于代谢应激时AMP激活的蛋白激酶（AMPK）和葡萄糖转运蛋白1（Glut1）的激活引起的，所以我们调查了TAM是否表达AMPK、Glut1以及其他代谢应激的指标pkm2。结果表明，TAM显著表达pkm2、Glut1和AMPK。 体外与4T1、EMT6和168共培养的骨髓源性巨噬细胞（BMDM）同样表现出pkm2、Glut1和AMPK的表达增加。此外，乳酸在这三种肿瘤中均高水平表达，在BMDM中引发了这些基因的表达，暗示乳酸可能在这些TAM中引发代谢应激反应。然而，这三种不同的乳腺癌模型受益于不同的靶向策略。巨噬细胞消除研究显示TAM促进了EMT6肿瘤的生长和4T1肿瘤的转移。靶向应激反应的整合应激反应抑制剂（ISRIB），它针对eIF2，影响了168肿瘤的进展，而ISRIB和针对乳酸脱氢酶的FX-11影响了4T1肿瘤的进展和转移。 总结这些数据表明，靶向TAM或早期肿瘤部位的代谢可以影响肿瘤的进展。然而，不同的反应变异性凸显了巨噬细胞的影响在三种不同的同基因乳腺癌模型中的差异。

Previously, we reported that tumor-associated macrophages (TAM) at early sites of mammary carcinoma showed a decrease in ATP production rate and a higher dependence on oxidative phosphorylation.Since these changes can result from activation of AMP-activated protein kinase (AMPK) and glucose transporter 1 (Glut1) during metabolic stress, we investigated whether the TAM showed increased expression of ampk and glut1, as well as another indicator of metabolic stress, pkm2. Indeed, the TAM exhibited significant expression of pkm2, glut1, and ampk.Bone marrow-derived macrophages (BMDM) co-cultured with 4T1, EMT6, and 168 in vitro similarly showed increased expression of pkm2, glut1, and ampk. Moreover, lactate, which is expressed at significant levels by all three tumors, induced expression of these same genes in BMDM suggesting that lactate may induce a metabolic stress response in these TAM. Yet, the three different mammary carcinoma models benefited from different targeting strategies. Macrophage depletion studies revealed that the TAM contributed to growth of the EMT6 tumor and metastasis of the 4T1 tumor. Targeting the stress response with the Integrated Stress Response Inhibitor (ISRIB), which targets eIF2, impacted 168 tumor progression, and ISRIB as well as FX-11, which targets lactate dehydrogenase, impacted 4T1 tumor progression and metastasis.Collectively, these data demonstrate that targeting TAM or metabolism at early tumor sites can impact tumor progression. However, variability in the responses underscore the fact that the impact of macrophages differs even within three different syngeneic mammary carcinoma models.