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Lung neuroendocrine cancer induces immunosuppressive macrophages via serotonin to drive resistance to the T cell engager tarlatamab

ABSTRACT: Tarlatamab, a DLL3/CD3-directed T-cell engager (TCE), provides clinical efficacy against small cell lung cancers (SCLCs), although its efficacy remains limited, indicating the importance of clarifying the resistance mechanism(s). Here, we show that serotonin (5-HT) produced by DLL3high neuroendocrine cancers (NECs) induces immunosuppressive tumor-associated macrophages (TAMs), resulting in impaired CD8+ T-cell function and TCE resistance. Using patient cohorts with SCLC and large cell neuroendocrine carcinoma (LCNEC), we found that DLL3high SCLCs induced immunosuppressive TAMs in the tumor microenvironment and became resistant to tarlatamab. DLL3high NECs increased 5-HT production via TPH1 upregulation. NEC-derived 5-HT augmented the immunosuppressive activity of 5-HT receptor 7 (HTR7)-expressing TAMs. Genetic ablation of HTR7 in TAMs or TPH1 in NECs restored CD8+ T-cell function and improved the efficacy of TCEs and PD-1 blockade. We propose that the NEC-derived 5-HT–HTR7 axis drives immunosuppressive TAM activation and TCE resistance, making it a key target to increase TCE efficacy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE345747 | GEO | 2026/09/29

REPOSITORIES: GEO

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