Plasma Histidine Levels Predict Response to Immune Checkpoint Inhibition

Metabolic pathways are known to modulate tumor immunogenicity, yet how metabolism influences the response to immune checkpoint inhibitors (ICI) remains unclear. In this study, Suissa, Fidelle, Reich, and colleagues used a multimodal machine learning framework to integrate unbiased patient metabolomics and clinical data and to identify metabolic determinants of response to ICI. Plasma and fecal metabolites from patients across 14 distinct cohorts with wide representation in cancer type, stage, and treatment were analyzed for association with clinical variables and treatment outcomes. Histidine, succinic acid, carnitine, docosatrienoic acid, hexadecanedioic acid, and creatinine were identified as positive predictors of progression-free survival, with plasma histidine levels displaying the strongest prognostic association. Importantly, the prognostic value of plasma histidine was validated in multiple independent cohorts. Extending these findings to high-risk cohorts, higher baseline histidine levels were found to predict a reduced risk of developing cancer among smokers. In murine orthotopic models, oral administration of L-histidine augmented the efficacy of ICI treatment, leading to tumor rejection. Additionally, L-histidine ingestion delayed tumor establishment and reduced aggressive features in the preventative setting. Histidine levels increased both in circulation and within tumor beds following uptake but decreased in fecal samples. Analysis of tumor-associated immune cells revealed that L-histidine stimulated proliferation of pre-effector CD8+ T cells in tumor-draining lymph nodes and effector CD8+ LAG3+ T cells within tumors. Mechanistically, histidine was found to increase mitochondrial respiration in CD8+ T cells cultured in low-nutrient conditions. Treatment with etomoxir, a CPT1a inhibitor, reduced oxygen consumption, indicating that histidine promotes CD8+ T-cell metabolism and proliferation in a manner dependent on fatty acid oxidation. Among patients with cancer, histidine consumption, but not plasma histidine levels, correlated with prolonged progression-free survival. Finally, fecal histidine levels were elevated in patients harboring a microbiome signature linked to favorable ICI response, while heightened levels of ImP, an immunosuppressive end-product of histidine catabolism, were identified in patients with gut dysbiosis and linked to poor outcomes. Altogether, this study combines rigorous integrated analyses of distinct patient cohorts with mechanistic preclinical investigation and suggests that profiling metabolites in plasma may aid in treatment selection, with histidine predicting favorable response to ICI.Suissa D, Fidelle M, Reich E, Pham T-N, Thomas S, Björk JR, et al. Metabolic determinants of cancer immunotherapy outcomes identified by plasma profiling. Nat Med 2026 Jun 25 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.