Single-cell and spatial transcriptomics reframe neuroendocrine neoplasm immunosuppression as multilayered and subtype-dependent.
Background
Neuroendocrine neoplasms (NENs) are a diverse group of tumors often considered "immune cold" and largely unresponsive to PD-1/PD-L1 checkpoint blockade, with few exceptions like Merkel cell carcinoma. The advent of advanced transcriptomic technologies, such as single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, has provided unprecedented detail into the NEN tumor microenvironment (TME). However, a unified, cross-subtype understanding of NEN immunosuppression leveraging these new insights has been lacking, hindering the development of more effective, targeted therapies.
Study Design
This study conducted a structured narrative review of PubMed-indexed literature up to April 30, 2026, to synthesize findings from single-cell and spatial transcriptomic studies of NENs. The review prioritized original human scRNA-seq, single-nucleus RNA-seq, spatial transcriptomic, and spatial proteomic studies. These primary data sources were supplemented by relevant mechanistic, clinical, and biomarker-focused reports to provide essential contextual information. The aim was to integrate these diverse findings across various NEN subtypes to reframe the understanding of NEN immunosuppression.
Results
Synthesis across pancreatic, pulmonary, gastrointestinal, cutaneous, pituitary, and adrenal NEN subtypes revealed conserved immunosuppressive features extending beyond the conventional PD-1/PD-L1 axis. Key findings include a prominent myeloid-dominated infiltration within the TME, often associated with alternative immune checkpoints such as VISTA, TIM-3, and Galectin-9. Furthermore, the review highlighted cancer-associated fibroblast-mediated immune exclusion as a significant mechanism contributing to the immune-cold phenotype. Lineage-state-dependent immune visibility was also identified, alongside direct immunomodulation by neuroendocrine secretory products, notably calcitonin gene-related peptide.
The review proposes a four-layer framework that integrates these complex mechanisms, linking them directly to emerging biomarkers and potential therapeutic strategies, including DLL3-directed bispecifics, alternative checkpoint inhibitors, stromal-targeting agents, and combinations with peptide receptor radionuclide therapy.
Key Findings
- NEN immunosuppression is a multilayered, subtype-dependent process, not simply 'immune cold'.
- Conserved features include myeloid-dominated infiltration with alternative checkpoints (VISTA, TIM-3, Galectin-9).
- Cancer-associated fibroblast-mediated immune exclusion is a key immunosuppressive mechanism.
- Neuroendocrine secretory products, like calcitonin gene-related peptide, directly immunomodulate the TME.
- A four-layer framework links these mechanisms to emerging therapies (DLL3 bispecifics, alternative checkpoint inhibitors).
Why It Matters
This comprehensive review fundamentally shifts the understanding of NEN immunosuppression, moving beyond a simplistic 'immune cold' classification to a nuanced, multilayered, and subtype-dependent process. Clinicians and researchers can now pursue biomarker-guided, subtype-adapted therapeutic strategies, rather than relying on broad, often ineffective, checkpoint blockade. This reframing opens new avenues for drug development, targeting specific mechanisms like alternative checkpoints, stromal components, or neuroendocrine secretory pathways. The proposed framework provides a conceptual scaffold for designing future clinical trials, potentially leading to more personalized and effective treatments for patients with these challenging tumors, improving response rates and patient outcomes.
neuroendocrine-neoplasms
tumor-microenvironment
immunosuppression
single-cell-rna-seq
spatial-transcriptomics
pd-1/pd-l1