Serotonin Transcriptional Axis Influences Immune Phenotypes and Outcomes in Lung Cancer

Background Neuromodulator-metabolite pathways are emerging regulators of tumor-immune interactions. A recent study showed that neurotransmitter signaling remodels immune infiltration. Building on this framework, we developed a serotonin transcriptional axis incorporating TPH/HTR synthesis, MAOA/IDO1 degradation, and SLC6A4 transport to characterize immune states in lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC). Methods TCGA RNA-seq data were processed via Xena. Row-z-scaled serotonin genes generated Up, Down, and composite Axis scores. k-means defined serotonin phenotypes. Immune checkpoints, cytotoxic programs, chemokines, and immune-cell surrogates (CD8A, FOXP3, NCAM1, IRF5, CD163, MS4A1, ITGAX) were assessed using Wilcoxon testing, correlation matrices, limma DEGs, Hallmark GSEA, and KM/Cox survival. AI tools (ChatGPT) were used for editing, grammar, and text condensation. Results In LUAD, three phenotypes emerged: C1 (MAOA/IDO1-high, immune-cold), C2 (serotonin-depleted), and C3 (TPH/HTR-high, immune-hot). C3 demonstrated strong activation of CD8A, IFNG, GZMB, PRF1, CXCL9/10/13 and checkpoints including PDCD1, CD274, CTLA4, LAG3, TIGIT (p<0.001). Serotonin Axis Score correlated positively with CD8 T cells, NK cells, dendritic cells, B cells, and M1 markers, and negatively with CD163, indicating an inflamed, antigen-presenting TME. GSEA showed C3 enrichment for interferon and inflammatory programs; C1 favored metabolic/MYC pathways. Survival differed significantly across clusters (p=0.0014), with C3 best and C1 worst; high serotonin axis trended toward improved OS (p=0.055).In LUSC, the same phenotypes recurred, confirming cross-histology reproducibility. C3 again showed the strongest immune activation with elevated cytotoxic and checkpoint expression. Serotonin activation associated with CD8A, NK signatures, MS4A1, ITGAX, and M1 markers, whereas serotonin suppression correlated with CD163-high M2 states. GSEA showed C3 enrichment for IFN-α/γ and inflammatory pathways; C1 enriched for OXPHOS/MYC programs. Cluster OS was not significant (p=0.63), but continuous Serotonin Axis Score predicted improved OS (p=0.039). Conclusions Serotonin pathway states reproducibly shape immune landscapes and survival across LUAD and LUSC. Serotonin activation aligns with cytotoxic infiltration, chemokine-rich inflammation, dendritic/B-cell signatures, M1 polarization, checkpoint expression, inflamed GSEA programs, and improved survival. These findings extend neuromodulator-TME concepts from recent study and identify the serotonin axis as a cross-histology biomarker and potential immunomodulatory target. Citation Format: Ecem Kalemoglu, Salih Akgun, Ayse Caner. A serotonin transcriptional axis shapes immune phenotypes and clinical outcomes in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5448.