Synergistic fluvastatin-nanotherapy suppresses DEPDC1-associated glycolysis and exosomal CCL2 to modulate the immune microenvironment in lung adenocarcinoma

Abstract Lung adenocarcinoma (LUAD), the predominant subtype of non-small cell lung cancer, is characterized by high incidence, poor prognosis, limited therapeutic efficacy. Glycolysis-high LUAD is associated with aggressive tumor behavior and immunosuppressive tumor microenvironment (TME) that broadly impairs anti-tumor immunity and therapeutic efficacy. Effective strategies targeting this metabolically aggressive phenotype are urgently needed. In this study, we developed a combination strategy that modulates DEPDC1-associated glycolysis by integrating fluvastatin (Fluv) with an integrin αVβ3-targeted photodynamic nanoplatform (cRGD-TPA-DCR-NP, with light irradiation; NPL), termed Fluv + NPL. Integrated multi-omics analyses, together with Western blotting and glycolytic rate (GlycoPER) measurements, demonstrated that Fluv + NPL suppressed DEPDC1-mediated NF-κB signaling, thereby inhibiting PI3K–AKT–mTOR pathway activity and reducing glycolytic metabolism in LUAD cells. Simultaneously, Fluv + NPL downregulated exosomal CCL2 levels and inhibited M2 macrophage polarization. In vivo studies further showed that Fluv + NPL effectively modulated the immune microenvironment of LUAD, as evidenced by enhanced M1 macrophage polarization, increased infiltration of effector T cells, and reduced M2 macrophage abundance, ultimately resulting in significant inhibition of LUAD growth. Collectively, our findings reveal an important role of DEPDC1 in linking glycolytic metabolism to immune regulation and establish Fluv + NPL as a promising therapeutic strategy that simultaneously suppresses glycolysis and enhances antitumor immunity through modulation of DEPDC1. These results provide new insights into glycolytic metabolism–immunity-based combination therapies for LUAD. Graphical Abstract