Plasma Histidine Linked to Cancer Immunotherapy Outcomes; Gut Microbiota Also Affect Interpretation
Background: Blood metabolites as clues to immunotherapy outcomes
Higher plasma histidine concentrations were associated with better survival outcomes after cancer immunotherapy across several patient cohorts. The researchers combined patient blood analyses with mouse and cell experiments to explore histidine’s effects on antitumor immunity. A clinical causal link showing that histidine supplementation improves treatment efficacy has not yet been established.
Immune checkpoint inhibitors benefit some patients with cancer, but the metabolic conditions that influence response remain poorly understood. Immune and tumor cells compete for nutrients, while gut microbiota also contribute to metabolite production and breakdown. Published in Nature Medicine, this study tracked changes in blood metabolites before and after treatment to examine whether they could be linked to prognosis.
Key findings: Repeated blood sampling captures an association between histidine and survival
The overall analysis included 4,336 plasma samples from 1,714 patients across 16 cohorts and five cancer types: lung, colorectal, kidney, bladder, and skin cancer. This was a longitudinal analysis that included repeated blood sampling early in treatment and during treatment.
Predictive model development used a training group of 105 patients and a separate 30-patient PANDORE validation group. The researchers analyzed 154 plasma metabolites measured by mass spectrometry, along with clinical variables, using DynForest, a longitudinal survival model. The final model retained eight predictors and used repeated measurements during treatment to predict 12-month progression-free survival (PFS). PFS is the time until disease progression or death.
In the validation group, the area under the receiver operating characteristic curve (AUC) was 0.731, with a 95% confidence interval of 0.512–0.949. AUC measures a model’s ability to discriminate between outcomes; this result also indicates substantial uncertainty because the validation sample was small. A comparison model using clinical variables alone had a reported AUC of 0.808, which does not support the superiority of the metabolite model. The researchers also examined associations between selected markers, including histidine, and clinical outcomes in seven external cohorts that included patients with cancer and people at high risk of developing cancer. This differs from validation demonstrating that the same predictive model’s AUC was reproduced across all cohorts.
In functional experiments, histidine supplementation enhanced the antitumor effects of immune checkpoint inhibitors in mouse tumor models. Mouse T cells cultured in vitro showed increased mitochondrial fatty acid oxidation after histidine treatment and better-maintained proliferative capacity under repeated stimulation. These findings support the possibility that histidine contributes to T-cell metabolism and function.
Implications and outlook: Dietary intake and blood levels need to be interpreted together
In the BIOBANK IO cohort of 147 patients with lung cancer, PFS was longer in the group with higher histidine intake estimated by dietary questionnaires. In a comparison using the cohort median of 1.25 g per 1,000 kcal of daily energy intake to divide the groups, the hazard ratio for disease progression or death was 0.64, with a 95% confidence interval of 0.43–0.96. This cutoff defined groups in an observational analysis; it is not a recommended intake. In the same cohort, plasma histidine was not significantly associated with PFS or overall survival.
Gut microbiota dysbiosis was associated with increased blood levels of imidazole propionate (ImP), a histidine breakdown product. No simple correlation was established between dietary intake and plasma histidine either, making it difficult to explain blood levels or treatment outcomes from intake alone. Findings from dietary surveys should be distinguished from randomized trials testing the effects of supplementation.
The researchers cited the small training and validation groups, clinical heterogeneity, and residual risk of false discoveries from analyzing many metabolites as limitations. Histidine is a candidate prognostic marker and a candidate for adjunctive therapy research, but prospective clinical studies are needed to establish its predictive value and therapeutic potential in patients.
Sources: Nature Medicine research article, Europe PMC full text.
Nature Medicine, Published online: 25 June 2026; doi:10.1038/s41591-026-04481-9Mass-spectrometry-based metabolomic analysis of plasma samples from multiple cohorts of patients treated with immunotherapy across five distinct tumor types, followed by machine learning enabled identification of metabolic signatures, as well as functional exploration, reveals association of increased plasma histidine levels with prolonged survival and its potential for therapeutic intervention.
This study identified candidate markers for assessing immunotherapy outcomes by tracking plasma metabolites alongside clinical information. Follow-up prospective studies could collect repeated measurements of histidine and related metabolites together with gut microbiota data, then assess predictive performance by cancer type and treatment. They should also determine whether adding metabolite testing to clinical information actually improves treatment decisions.
Mouse and cell experiments provide a research basis for histidine supplementation, but its treatment efficacy and safety in patients with cancer require separate evaluation. The intake cutoff from the dietary survey should not be used as a prescribed dose, and blood levels alone should not yet guide the selection or discontinuation of immunotherapy. Clinical trials that account for how gut microbiota break down histidine are the next task in developing adjunctive therapy.