Serotonin Metabolism Shapes the Tumor Immune Microenvironment and Serves as a Therapeutic Target in Lung Cancer

Lung cancer progression involves complex interactions between metabolic pathways and the immune microenvironment. The role of serotonin, a tryptophan-derived metabolite, in immune responses to lung tumors remains unclear.

An orthotopic lung cancer model was established by intravenously injecting KP (KrasG12D/p53-/-) cells into C57BL/6 mice. Metabolomic and flux analyses were conducted on tumor versus normal lung tissues. Serotonin was administered to tumor-bearing mice, followed by immunofluorescence and flow cytometry to assess immune responses. Human lung cancer datasets were analyzed to validate clinical relevance.

Tumor tissues exhibited a significant decrease in serotonin levels. Although tryptophan, serotonin, and kynurenine levels were decreased overall, flux analysis revealed a metabolic shift favoring kynurenine synthesis, with a ~10-fold increase in the kynurenine-to-serotonin ratio. Serotonin supplementation significantly prolonged survival and enhanced dendritic cell and CD8⁺ T cell infiltration and activation in tumors. Analysis of public datasets showed that serotonin expression positively correlated with CD8⁺ T cell activation signatures and patient prognosis.

By revealing serotonin as a potential biomarker and therapeutic target, this study paves new avenues for improving lung cancer treatment strategies through modulation of the immune microenvironment. Moreover, the precise receptor-mediated mechanisms underlying serotonin's immunomodulatory effects remain to be clarified, and translational validation in human tissues is warranted to strengthen clinical relevance.

Serotonin deficiency in the tumor microenvironment of the lung suppresses antitumor immunity. Its restoration reverses immune dysfunction and limits tumor progression. These findings identify serotonin as a potential metabolic regulator and immunotherapeutic target in lung cancer.