Advances in understanding the tumor microenvironment of neuroendocrine prostate cancer

Neuroendocrine prostate cancer (NEPC) is an aggressive, treatment-refractory phenotype of advanced prostate cancer. This narrative review was informed by targeted searches of PubMed, Web of Science through May 2026. We classify evidence as Level A (human NEPC samples or clinical cohorts), Level B (NEPC-specific models), Level C (prostate adenocarcinoma or CRPC without NEPC resolution), or Level D (pan-cancer or non-prostate extrapolation), and apply these levels to central claims and a study-level evidence table. Direct human data support immune depletion in most NEPC tumors, with heterogeneous macrophage, fibroblast and lymphoid remodeling in selected cohorts; model studies support context-dependent cytokine, hypoxic, extracellular-matrix and metabolic effects on lineage plasticity. By contrast, CAF-derived lactate fueling NEPC, a dense collagen drug barrier, and NEPC-specific vascular permeability remain unvalidated. Most TME-directed treatments are preclinical or extrapolated, whereas DLL3-directed therapy has shown early activity in biomarker-selected disease. Longitudinal biopsies, spatial multi-omics, humanized models and biomarker-defined trials are needed to distinguish causal vulnerabilities from correlates of treatment-emergent lineage transition.