A metabolically reprogrammable nanoplatform potentiates photodynamic immunotherapy through glycolytic blockade

Tumor glycolysis supports malignant progression and promotes an immunosuppressive microenvironment, but glycolysis blockade alone often gives limited therapeutic benefit because tumor cells can adapt metabolically and metabolic inhibition does not necessarily elicit antitumor immunity. Here, we report a metabolically reprogrammable nanoplatform, TCP@PRL3 nanoparticles (TCP@PRL3 NPs), integrating an aggregation induced emission photosensitizer with a phosphatase of regenerating liver 3 (PRL3) inhibitor for combined photodynamic and immunometabolic therapy. Upon irradiation, TCP@PRL3 NPs generated reactive oxygen species (ROS) to induce immunogenic cell death (ICD), while PRL3 inhibition suppressed glycolysis, reduced lactate production, and alleviated tumor acidification. In multiple myeloma (MM) cells, TCP@PRL3 NPs decreased adenosine triphosphate (ATP) and lactate levels, downregulated pyruvate kinase M2 (PKM2), and inhibited extracellular acidification and oxygen consumption. These metabolic changes promoted dendritic cell maturation, reduced senescent T cell populations, expanded activated CD27⁺CD28⁺ T cells, and increased secretion of interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin 2 (IL-2). In a humanized MM model, TCP@PRL3 NPs markedly inhibited tumor growth, and combination with daratumumab further improved efficacy without evident systemic toxicity. The platform also suppressed CT26 and 4T1 tumors by enhancing dendritic cell activation, CD8⁺ T cell responses, and intratumoral metabolic remodeling. These findings identify TCP@PRL3 NPs as a promising immunometabolic nanoplatform for metabolically active tumors.