Metabolomic profiling reveals plasma LPC as an indicator of systemic inflammation and immunotherapy response in squamous cell carcinoma

Cancer is increasingly recognized as a systemic disease characterized not only by local tumor growth but also by widespread metabolic and immunologic disturbances that shape disease progression and treatment response. To clarify systemic metabolic alterations associated with prognosis and immune checkpoint inhibitor (ICI) efficacy in squamous cell carcinoma (SCC), we conducted an integrated multi-omics analysis of plasma from 149 patients with advanced or recurrent esophageal or head and neck SCC. Targeted metabolomics quantified 635 metabolites, which were combined with detailed clinical, proteomic, and cytokine datasets. Weighted gene correlation network analysis revealed a single metabolite group-lysophosphatidylcholines (LPCs)-as most strongly associated with the Glasgow Prognostic Score, a marker of systemic inflammation and patient survival. Across nearly all measurable LPC species, plasma levels were markedly reduced in patients with elevated inflammatory burden and poor prognosis. LPC concentrations showed minimal correlation with tumor size, treatment line, or performance status, indicating that LPC reduction reflects host systemic conditions rather than tumor burden or treatment exposure. Survival analysis demonstrated that patients with low LPC levels had significantly shorter overall survival, with the strongest association observed in those receiving ICIs. Among ICI-treated patients, especially those treated in the first-line setting, low LPC levels identified individuals with minimal therapeutic benefit, whereas LPC levels were not prognostic in patients never exposed to ICIs. To explore the biological context of LPC loss, we analyzed plasma proteomic and cytokine profiles. Proteomic signatures in the low-LPC group revealed enrichment of pathways related to inflammation, innate immunity, and coagulation activation; levels of CRP, serum amyloid A, and other acute-phase reactants were substantially increased. Cytokine profiling demonstrated that low LPC levels were accompanied by elevated IL-6, IL-10, and TNF-alpha, further supporting the presence of systemic chronic inflammation. Conversely, chemokines such as CCL2 and CXCL8 were higher in patients with preserved LPC levels. Together, these multi-omics findings indicate that decreased LPC marks a systemic pro-inflammatory and immunosuppressive state that undermines antitumor immunity and reduces responsiveness to PD-1 blockade.