Simple Summary
Cancers of the chest, including lung, esophageal, pleural, and thymic tumors, remain among the most difficult cancers to treat. These tumors rewire the way they use nutrients such as sugars, amino acids, and fats to grow, evade the immune system, and survive treatment. Metabolomics is a laboratory approach that measures these small molecules in tumors, blood, and other body fluids, and related methods can track how nutrients are used inside a living tumor. This review explains what these tools can and cannot show, summarizes what they have revealed about each type of chest cancer, and asks whether they can help detect cancer earlier, predict who will benefit from treatment, and guide drugs aimed at tumor metabolism. It also explains why most findings are not yet ready for routine patient care and what would be needed to change that.
Abstract
Thoracic malignancies show context-dependent metabolic plasticity that influences growth, immune evasion, and treatment response. This review examines how metabolomics, stable-isotope tracing, and metabolic flux analysis complement molecular profiling in lung, esophageal, pleural, and thymic cancers. We distinguish metabolite abundance from isotope enrichment and quantitative flux, and review analytical platforms, computational workflows, histology-specific programs, immunometabolism, biomarkers, and therapy. Lung squamous cell carcinoma often depends on glycolysis, lung adenocarcinoma shows substrate and spatial heterogeneity, and molecular subsets of small cell lung cancer have preclinical vulnerabilities in arginine metabolism and guanosine nucleotide synthesis. Hypoxia and metabolite exchange among malignant, stromal, and immune cells may shape therapeutic resistance. Biofluid and tissue studies support early detection and monitoring, but most circulating signatures and findings in rare thoracic tumors remain exploratory. Translation is limited by confounding, incomplete metabolite identification, small cohorts, and limited external validation. Trials of unselected metabolic inhibitors have largely failed. Two biomarker-selected strategies have advanced: arginine deprivation in non-epithelioid pleural mesothelioma, a population enriched for argininosuccinate synthetase 1 (ASS1) deficiency, and PRMT5 inhibition in tumors with MTAP deletion. These results suggest that success may depend on selecting patients by a demonstrated metabolic dependency rather than by the plausibility of the target. Progress requires harmonized multicenter workflows, paired tissue and biofluid sampling, rigorous validation, and integration with spatial, single-cell, multi-omic, and clinical data.