Summary Effective therapies are lacking for patients with advanced colorectal cancer (CRC). The CRC tumor microenvironment has elevated metabolic waste products due to altered metabolism and proximity to the microbiota. The role of metabolite waste in tumor development, progression, and treatment resistance is unclear. We generated an autochthonous metastatic mouse model of CRC and used unbiased multiomic analyses to reveal a robust accumulation of tumoral ammonia. The high ammonia levels induce T cell metabolic reprogramming, increase exhaustion, and decrease proliferation. CRC patients have increased serum ammonia, and the ammonia-related gene signature correlates with altered T cell response, adverse patient outcomes, and lack of response to immune checkpoint blockade. We demonstrate that enhancing ammonia clearance reactivates T cells, decreases tumor growth, and extends survival. Moreover, decreasing tumor-associated ammonia enhances anti-PD-L1 efficacy. These findings indicate that enhancing ammonia detoxification can reactivate T cells, highlighting a new approach to enhance the efficacy of immunotherapies.
摘要 晚期结直肠癌（CRC）患者缺乏有效的治疗手段。由于新陈代谢的改变和与微生物群的接近，CRC肿瘤微环境中的代谢废物升高了。代谢废物在肿瘤发展、进展和治疗抗性中的作用尚不清楚。我们产生了一个CRC的自体转移小鼠模型，并使用无偏见的多组学分析来揭示肿瘤氨的大量积累。高浓度的氨诱导T细胞代谢重编程，增加衰竭，并减少增殖。癌症患者的血清氨增加，氨相关的基因特征与T细胞反应的改变、患者的不良后果以及对免疫检查点阻断的缺乏反应有关。我们证明，加强氨的清除可以重新激活T细胞，减少肿瘤的生长，并延长生存期。此外，减少肿瘤相关的氨增强了抗PD-L1的疗效。这些发现表明，增强氨的解毒作用可以重新激活T细胞，突出了一种增强免疫疗法疗效的新方法。
