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-mPEG 2000 -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 ( 1 O 2 ) 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. This schematic illustrates a synergistic anti-HCC therapy: laser-triggered ROS from PB-4 induces ICD, while SK inhibits PKM2, integrating PDT/PTT with metabolic-immune modulation. • A novel NIR photosensitizer (PB-4) with a non- -conjugated structure was developed, exhibiting intrinsic NIR emission for deep-tissue synergistic PDT/PTT and dual-modal imaging. • The nanosystem creates cooperative action: PB-4-generated ROS induces ICD while SK inhibits PKM2, with mutual reinforcement (ROS enhances PKM2 inhibition, SK downregulates HSP70). • SK-mediated PKM2 inhibition disrupts glycolysis, alleviating hypoxia and downregulating HIF-1 to amplify the PDT efficacy initiated by PB-4-derived ROS. • This work integrates a TCM-derived metabolite with nanotechnology, establishing a paradigm of phototherapy, metabolic modulation, and immune activation for synergistic HCC treatment.