Self-assembled ferric-shikonin-quercetin (FSQ) nanoparticles co-delivering R848 enable lactate reduction, ICD induction, and immune modulation in vitro.

To overcome inadequate tumor immunogenicity and the immunosuppressive tumor microenvironment, a self-assembled nanomedicine (R848@FSQ) is developed by coordinating the chemotherapeutic drugs shikonin (SHK) and quercetin (Qu) with Fe3 + to form a metal-phenolic network (MPN), and is simultaneously loaded with the immune adjuvant resiquimod (R848) via hydrophobic interactions. Encapsulated SHK inhibits aerobic glycolysis by targeting pyruvate kinase M2 (PKM2), thereby reducing lactate production and inducing immunogenic cell death (ICD). In combination with the co‑loaded R848, this effect repolarizes tumor-associated macrophages (TAMs) and further remodels the immunosuppressive metabolic tumor microenvironment. Concurrently, Qu downregulates the expression of heat shock protein 70 (HSP70), attenuating immune resistance of tumor cells and promoting apoptotic responses. This nanomedicine demonstrates potent capabilities in tumor chemotherapy, modulation of the immunosuppressive tumor microenvironment, and attenuation of tumor cell immune resistance, offering a novel approach for synergistic chemotherapy and immunotherapy.