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

DLL3-high small cell lung cancers and large cell neuroendocrine carcinomas induce immunosuppressive tumor-associated macrophages that impair CD8+ T cell function and drive resistance to tarlatamab.

• Why it matters: Tarlatamab efficacy in small cell lung cancers is limited, so resistance mechanisms in the tumor microenvironment need clarification to improve TCE outcomes.
• What they did: In SCLC and large cell neuroendocrine carcinoma cohorts, DLL3-high neuroendocrine cancers upregulate TPH1 to increase serotonin (5-HT), which activates HTR7-expressing TAMs; HTR7 ablation in TAMs or TPH1 ablation in NECs restores CD8+ T cell function and improves TCE and PD-1 blockade efficacy.
• The result: The NEC-derived 5-HT–HTR7 axis is linked to immunosuppressive TAM activation and tarlatamab resistance, suggesting a target to increase TCE efficacy.