Multi-omics Profiling of Pancreatic Neuroendocrine Tumors: Interplay of Genomic Instability and the Tumor Microenvironment (Review).

Pancreatic neuroendocrine tumors (PNETs) represent a biologically heterogeneous group of neoplasms shaped by both intrinsic genomic alterations and dynamic interactions with the tumor microenvironment (TME). Conventional analytical approaches offered limited insight into these complex mechanisms. However, the emergence of multi-omics technologies including genomics, transcriptomics, proteomics and spatial single-cell platforms dramatically expanded current understanding of tumor evolution, immune-stromal crosstalk and phenotypic plasticity. In the present review, findings from novel multi-omics studies were integrated to reframe PNET biology through the perspective of TME co-evolution. The present review highlighted how genomic instability serves as a key driver, promoting transcriptomic reprogramming and clonal evolution that subsequently remodels the TME into an immunosuppressive niche rich in cancer-associated fibroblasts and characterized by immune exclusion. The present review further emphasized the novel role of spatial multi-omics in deciphering the spatial heterogeneity of the PNET ecosystem. These insights accelerated the identification of novel biomarkers and revealed novel therapeutic susceptibilities, potentially paving the way for rational combination strategies that target both tumor-intrinsic pathways and microenvironmental constraints. Therefore, the present review proposed that multi-omics profiling provides not only a descriptive landscape but a mechanistic framework for precision oncology, enabling improved patient stratification and biomarker-driven therapeutic interventions in PNETs.