Cancer Metabolomics and T-Cell Immunotherapy

Adoptive T-cell therapies and immune checkpoint inhibitors have transformed the treatment of several malignancies, yet durable responses remain confined to a minority of patients. A growing body of evidence points to the tumor metabolic microenvironment as a central reason for this gap. Tumor cells compete with infiltrating lymphocytes for glucose, glutamine, and essential amino acids, while accumulating lactate, adenosine, kynurenine, and lipid species that blunt effector function. Under these conditions, T cells undergo mitochondrial dysfunction, impaired oxidative phosphorylation, and progressive exhaustion, limiting the efficacy of both endogenous and engineered antitumor responses.Metabolomics has emerged as the analytical bridge between these observations and actionable intervention. Advances in mass spectrometry, spatial metabolic imaging, stable-isotope flux analysis, and single-cell metabolic profiling now make it possible to resolve metabolite gradients within tumors, track substrate use in specific immune populations, and identify circulating metabolic signatures associated with treatment response. In parallel, metabolic reprogramming of CAR-T and TCR-T products, dietary and microbiome-directed interventions, and pharmacological targeting of metabolic checkpoints are being tested as ways to restore T-cell fitness.Despite this momentum, significant gaps persist. Metabolomic findings are frequently descriptive rather than causal, spatial and temporal resolution within the tumor microenvironment remains limited, candidate metabolic biomarkers are rarely validated in independent cohorts, and translation from murine models to patients has been inconsistent.This Research Topic aims to bring together mechanistic, translational, and clinical research that connects cancer metabolomics to the success or failure of T-cell immunotherapy. We seek contributions that move beyond correlation toward causal understanding and clinical application — work that identifies which metabolic constraints matter, how they can be measured reliably, and how they can be overcome to improve patient outcomes.We welcome Original Research, Brief Research Reports, Reviews, Mini Reviews, Methods, Clinical Trials, and Perspectives addressing, but not limited to:1. Metabolic competition in the tumor microenvironment — nutrient depletion, hypoxia, acidosis, and their effects on T-cell differentiation, persistence, and exhaustion2. Immunosuppressive metabolites — lactate, adenosine, kynurenine, oxysterols, short-chain fatty acids, and polyamines as regulators of effector and regulatory T-cell function3. Mitochondrial and lipid metabolism in T cells — determinants of memory formation, stemness, and long-term persistence of adoptively transferred cells4. Metabolic engineering of cellular therapies — approaches to improve the metabolic fitness of CAR-T, TCR-T, and TIL products, including manufacturing conditions and genetic modification5. Analytical and spatial methods — spatial metabolomics, mass spectrometry imaging, single-cell metabolic profiling, stable-isotope tracing, and multi-omics integration applied to immune-infiltrated tumors6. Metabolic biomarkers of response and resistance — circulating or intratumoral metabolomic signatures predicting outcomes with checkpoint blockade or cell therapy, ideally with independent cohort validation7. Therapeutic modulation — pharmacological metabolic inhibitors, dietary interventions, fasting-mimicking regimens, and microbiome-directed strategies combined with T-cell immunotherapy8. Metabolic determinants of toxicity — metabolic contributors to cytokine release syndrome, immune-related adverse events, and their managementTopic Editor Francesco Manfredi is employed by Neurimmune AG. Topic Editor. Christian Pellegrino is employed by Philochem AG. All other Topic Editors declare no competing interests with regard to the Research Topic subjectManuscripts consisting solely of bioinformatics or computational analysis of public genomic, transcriptomic, or metabolomic databases, without robust and relevant validation (an independent clinical or patient cohort, or biological validation in vitro or in vivo not derived from public databases), are out of scope for this Research Topic. Purely descriptive metabolite profiling without a functional or clinical link to T-cell immunity is also outside the scope. Topic editors: Francesco Manfredi, Sara Granja, Christian Pellegrino, Teresa Olbrich Source: https://www.frontiersin.org/research-topics/84573/cancer-metabolomics-and-t-cell-immunotherapy