Ji Zheng

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.

An Integrated Cell-Death Program Defines Aggressive Prostate Cancer by Coupling Ezrin to the Hippo-YAP/TAZ Axis.

Spatiotemporally Controlled Lysosomal Membrane Permeabilization Amplifies STING-Driven Antitumor Immunity in Prostate Cancer.

Prostate cancer (PCa) remains a major clinical challenge due to therapeutic resistance and immunologically cold tumor microenvironment. Lysosomal membrane permeabilization (LMP)-induced lysosome-dependent cell death offers an alternative route to eliminate resistant tumor cells and initiate immunogenic cell death, yet its efficacy is often limited by insufficient spatiotemporal control and immune activation. Here, we report a spatiotemporally programmable supramolecular nanoplatform (Cu-P-MSA) that integrates lysosome-targeted sonodynamic therapy with tumor-confined innate immune activation for PCa treatment. Cu-P-MSA is a modular self-assembling peptide incorporating a PSMA-targeting ligand, morpholine moiety, and cathepsin B-cleavable linker, enabling tumor-selective uptake and in situ formation of fibrous sonosensitizer depots within lysosomes. Upon ultrasound irradiation, a glutathione-responsive open-shell sonosensitizer induces controlled LMP, simultaneously activating ferroptosis and pyroptosis and promoting immunogenic cell death. Meanwhile, tumor-specific release of a STING agonist MSA-2 elicits robust type I interferon responses, driving dendritic cell maturation and cytotoxic T-cell infiltration. This coordinated lysosomal disruption-immune amplification strategy effectively reprograms the tumor immune microenvironment and suppresses both primary and distant tumors, with inhibition rates reaching 84.3% and 77.5%, respectively. Overall, this work establishes a spatiotemporally controlled supramolecular approach that integrates lysosomal disruption with innate immune activation to overcome therapeutic resistance and immunosuppression in PCa.