Metabolic-photoimmunotherapy: A Shikonin-NIR-I photosensitizer nanoplatform reprograms glycolysis to potentiate phototherapy-induced antitumor immunity in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains a formidable clinical challenge, plagued by a profoundly immunosuppressive tumor microenvironment (TME) and high recurrence rates (50-70%). In this study, we developed a multifunctional DSPE-mPEG2000-based nanoplatform (PB-4@SK NPs) to co-deliver Shikonin (SK), a potent glycolytic inhibitor, and PB-4, a novel first near-infrared (NIR-I) polymeric photosensitizer. This nanoplatform enables a synergistic metabolic-photoimmunotherapy paradigm that transcends the limitations of conventional monotherapies. Upon 660 nm laser irradiation, PB-4 mediates robust dual-mode phototherapy via concurrent photodynamic and photothermal effects, generating singlet oxygen (1O2) and localized hyperthermia to trigger potent immunogenic cell death (ICD). Simultaneously, the targeted release of SK suppresses the Pyruvate Kinase M2/hypoxia-inducible factor 1α (PKM2/HIF-1α) signaling axis, thereby reversing the Warburg effect and alleviating tumor hypoxia. A self-amplifying feedback loop is established: PB-4-derived ROS reinforce SK-mediated metabolic inhibition, while SK-mediated Heat shock protein 70(HSP70) suppression attenuates cytoprotective thermoresistance, collectively maximizing apoptotic responses. Our findings demonstrate that PB-4@SK NPs effectively remodel the TME by polarizing M2 macrophages toward the M1 phenotype, enhancing CD8+ T cell infiltration, and, crucially, inducing robust long-term immune memory. This rationally designed strategy provides a promising and translationally relevant approach for eradicating primary tumors and preventing post-treatment relapse in HCC.