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

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Neuroendocrine neoplasms (NENs) are often considered "immune cold" and resistant to PD-1/PD-L1 blockade.
• Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics offer new insights into the NEN tumor microenvironment (TME).

Purpose of the Study:

• To integrate scRNA-seq and spatial transcriptomic data across NEN subtypes.
• To reframe the understanding of NEN immunosuppression.
• To identify translational implications for NEN treatment.

Main Methods:

• Structured narrative review of PubMed-indexed studies up to April 2026.
• Prioritization of human scRNA-seq, single-nucleus RNA-seq, spatial transcriptomic, and spatial proteomic studies.
• Inclusion of mechanistic, clinical, and biomarker-focused reports.

Main Results:

• Conserved immunosuppressive features across NEN subtypes (pancreatic, pulmonary, GI, etc.) beyond PD-1/PD-L1.
• Myeloid infiltration with alternative checkpoints (VISTA, TIM-3, Galectin-9).
• Cancer-associated fibroblast-mediated immune exclusion and neuroendocrine secretory product immunomodulation.

Conclusions:

• NEN immunosuppression is a complex, multilayered, and subtype-dependent process.
• A four-layer framework integrates mechanisms, biomarkers, and therapies.
• These findings support biomarker-guided, subtype-adapted therapeutic strategies in neuroendocrine oncology.