A Triple Threat Against Ovarian Cancer: Os(II)-Pt(IV)-Ceritinib Conjugates for Photodynamic Therapy, Chemotherapy, and Immunogenic Cell Death Induction

Metal-based anticancer agents offer unique opportunities to integrate multiple therapeutic modalities within a single molecular framework. Herein, we present the first Osmium(II)-Platinum(IV)-Ceritinib conjugate (Os-Pt-Cer) that synergistically combines photodynamic therapy (PDT), chemotherapy, and immunotherapy via immunogenic cell death (ICD) induction. This heterobimetallic complex features a photoactive osmium(II) polypyridyl core, a platinum(IV) prodrug derived from oxaliplatin, and the kinase inhibitor ceritinib as an axial ligand. Upon deep-red irradiation (λ = 740 nm), the conjugate exhibits potent antiproliferative activity in ovarian 2D cancer cells and 3D tumour spheroids, with IC₅₀ values in the low nanomolar range. In addition, Os-Pt-Cer effectively inhibits cancer cell migration. Mechanistic studies reveal that the conjugate induces hallmarks of ICD, including calreticulin exposure, ATP release, HMGB1 secretion and phagocytosis. This multifunctional approach highlights the potential of osmium(II)-platinum(IV) conjugates as promising candidates for overcoming resistance and immune evasion in high-grade ovarian carcinoma.