Metabolic determinants of cancer immunotherapy outcomes identified by plasma profiling
Abstract
Immune-checkpoint inhibitors benefit a subset of patients with advanced cancer, and the metabolic determinants of response remain unclear. Here, using targeted metabolomics and metagenomics, we profiled 4,336 plasma samples from 1,714 patients across five tumor types and 16 cohorts spanning Europe and North America, longitudinally sampled during five immune-checkpoint inhibitor-based treatment modalities, including fecal microbiota transplantation. A multimodal machine-learning framework integrating 154 metabolites with clinical variables identified five metabolites, age, body mass index and renal function as predictors of 12-month progression-free survival. The model achieved areas under the curve of 0.88 in training and 0.73 in validation cohorts of 105 and 30 patients, respectively and generalized across seven external cohorts. Histidine was a favorable prognostic feature of survival, whereas long-chain fatty acids and succinate were negatively associated with outcome. Histidine supplementation enhanced antitumor immunity in mice. Histidine-rich diets improved progression-free survival in patients lacking dysbiotic microbiome signatures associated with histidine catabolism.
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BibTeX
@article{suissa2026metabolic,
title = {{Metabolic determinants of cancer immunotherapy outcomes identified by plasma profiling}},
author = {Déborah Suissa and Marine Fidelle and Ella Reich and Thao-Nguyen Pham and Simon Thomas and Johannes R Björk and Peng Liu and Liwei Zhao and Koji Kitaoka and Eléonore Piard and Isabelle Lebhar and Ai-Ling Tian and Cassandra Thelemaque and Carolina Alves Costa Silva and Eric Deutsch and Yohann Loriot and Nicola Segata and Gianmarco Piccinno and Geke a P Hospers and Saman Maleki Vareki and Michael S Silverman and John G Lenehan and Véronique Bataille and David Boulate and Tatiana Kuznetsova and Rinse K Weersma and Meriem Messaoudene and Sylvère Durand and Carlijn M van der Aalst and Harry J de Koning and Beatrice Schuler-Thurner and I Jolanda M de Vries and Edmond Rafie and Renée Maria Saliby and Marc Machaalani and Sebastian Haferkamp and Bastian Schilling and Serena Porcari and Chiara Ciccarese and Roberto Iacovelli and Chiara Cremolini and Toni K Choueiri and Arielle Elkrief and Guido Kroemer and Lucie Heinzerling and Kenji Chamoto and Gianluca Ianiro and Bertrand Routy and Lisa Derosa and Nikos Paragios and Laurence Zitvogel},
journal = {Nature Medicine},
year = {2026},
month = sep,
doi = {10.1038/s41591-026-04481-9},
url = {https://hal.science/hal-05738783v1},
note = {CC BY-NC-SA 4.0},
}
RIS
TY - JOUR
TI - Metabolic determinants of cancer immunotherapy outcomes identified by plasma profiling
AU - Déborah Suissa
AU - Marine Fidelle
AU - Ella Reich
AU - Thao-Nguyen Pham
AU - Simon Thomas
AU - Johannes R Björk
AU - Peng Liu
AU - Liwei Zhao
AU - Koji Kitaoka
AU - Eléonore Piard
AU - Isabelle Lebhar
AU - Ai-Ling Tian
AU - Cassandra Thelemaque
AU - Carolina Alves Costa Silva
AU - Eric Deutsch
AU - Yohann Loriot
AU - Nicola Segata
AU - Gianmarco Piccinno
AU - Geke a P Hospers
AU - Saman Maleki Vareki
AU - Michael S Silverman
AU - John G Lenehan
AU - Véronique Bataille
AU - David Boulate
AU - Tatiana Kuznetsova
AU - Rinse K Weersma
AU - Meriem Messaoudene
AU - Sylvère Durand
AU - Carlijn M van der Aalst
AU - Harry J de Koning
AU - Beatrice Schuler-Thurner
AU - I Jolanda M de Vries
AU - Edmond Rafie
AU - Renée Maria Saliby
AU - Marc Machaalani
AU - Sebastian Haferkamp
AU - Bastian Schilling
AU - Serena Porcari
AU - Chiara Ciccarese
AU - Roberto Iacovelli
AU - Chiara Cremolini
AU - Toni K Choueiri
AU - Arielle Elkrief
AU - Guido Kroemer
AU - Lucie Heinzerling
AU - Kenji Chamoto
AU - Gianluca Ianiro
AU - Bertrand Routy
AU - Lisa Derosa
AU - Nikos Paragios
AU - Laurence Zitvogel
PY - 2026
DA - 2026/09/04
JO - Nature Medicine
DO - 10.1038/s41591-026-04481-9
UR - https://hal.science/hal-05738783v1
AB - Immune-checkpoint inhibitors benefit a subset of patients with advanced cancer, and the metabolic determinants of response remain unclear. Here, using targeted metabolomics and metagenomics, we profiled 4,336 plasma samples from 1,714 patients across five tumor types and 16 cohorts spanning Europe and North America, longitudinally sampled during five immune-checkpoint inhibitor-based treatment modalities, including fecal microbiota transplantation. A multimodal machine-learning framework integrating 154 metabolites with clinical variables identified five metabolites, age, body mass index and renal function as predictors of 12-month progression-free survival. The model achieved areas under the curve of 0.88 in training and 0.73 in validation cohorts of 105 and 30 patients, respectively and generalized across seven external cohorts. Histidine was a favorable prognostic feature of survival, whereas long-chain fatty acids and succinate were negatively associated with outcome. Histidine supplementation enhanced antitumor immunity in mice. Histidine-rich diets improved progression-free survival in patients lacking dysbiotic microbiome signatures associated with histidine catabolism.
SN - 1078-8956
SN - 1744-7933
ER -