Single-Cell and Spatial Transcriptomics Reframe the Immunosuppressive Microenvironment of Neuroendocrine Neoplasms

Neuroendocrine neoplasms (NENs) are a heterogeneous family of tumors that have traditionally been regarded as "immune cold" and largely refractory to PD-1/PD-L1 checkpoint blockade, with notable exceptions such as Merkel cell carcinoma (MCC). The advent of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics has enabled unprecedented dissection of the NEN tumor microenvironment (TME), but a cross-subtype synthesis is lacking. This review aims to integrate single-cell and spatial transcriptomic findings across major NEN subtypes to reframe NEN immunosuppression and delineate translational implications. To this end, we performed a structured narrative review of PubMed-indexed studies up to 30 April 2026, prioritizing original human scRNA-seq, single-nucleus RNA-seq, spatial transcriptomic, and spatial proteomic studies of NENs, supplemented by mechanistic, clinical, and biomarker-focused reports providing essential context. Across these studies, synthesis spanning pancreatic, pulmonary, gastrointestinal, cutaneous, pituitary, adrenal, and other NEN subtypes highlights conserved features beyond the PD-1/PD-L1 axis, including myeloid-dominated infiltration with alternative checkpoints (VISTA, TIM-3, Galectin-9), cancer-associated fibroblast-mediated immune exclusion, lineage-state-dependent immune visibility, and direct immunomodulation by neuroendocrine secretory products such as calcitonin gene-related peptide. We propose a four-layer framework integrating these mechanisms and linking them to emerging biomarkers and therapies, including DLL3-directed bispecifics, alternative checkpoint inhibitors, stromal-targeting agents, and peptide receptor radionuclide therapy combinations. Together, these findings indicate that single-cell and spatial transcriptomic studies reframe NEN immunosuppression as a multilayered, subtype-dependent process, providing a conceptual scaffold for biomarker-guided, subtype-adapted therapeutic strategies and prospective clinical trial design in neuroendocrine oncology.