Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer

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 multi-omic 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.

Automated summary

There is a lack of effective therapies for advanced colorectal cancer (CRC) patients. In the CRC tumor microenvironment, there is an accumulation of metabolic waste products, such as ammonia, due to altered metabolism and proximity to the microbiota. The role of metabolite waste in tumor development, progression, and treatment resistance is not well understood. This study demonstrates that high ammonia levels induce T cell metabolic reprogramming, leading to T cell exhaustion and decreased proliferation. Enhancing ammonia clearance can reactivate T cells and enhance the efficacy of immunotherapies.