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

Tarlatamab, a delta-like protein 3 (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 mechanisms. 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 SCLC and large cell neuroendocrine carcinoma cohorts, we find that DLL3high SCLCs induce immunosuppressive TAMs in the tumor microenvironment and become resistant to tarlatamab. DLL3high NECs increase 5-HT production via TPH1 upregulation. NEC-derived 5-HT augments the immunosuppressive activity of 5-HT receptor 7 (HTR7)-expressing TAMs. Genetic ablation of HTR7 in TAMs or TPH1 in NECs restores CD8+ T cell function and improves the efficacy of TCEs and programmed cell death protein 1 (PD-1) blockade. We propose that NEC-derived 5-HT-HTR7 axis drives immunosuppressive TAM activation and TCE resistance, making it a key target to increase TCE efficacy.