An efficient ICD inducer based on Ir(III) cyclometalated complex for anticancer and anti-migration effects towards cisplatin-resistant cancer cells

The clinical use of metal-based anticancer drugs is constrained by challenges like significant side effects and the development of drug resistance. In recent years, metal-based immunogenic cell death (ICD) inducers have attracted significant research interest for their potential in both chemotherapy and immunotherapy. Herein, we present a novel cyclometalated iridium(III) complex Ir-NPX with the COX-2 inhibitor naproxen (NPX) as a ligand, serving as an ICD inducer. Ir-NPX not only showed remarkable antitumor efficacy, notably in targeting cisplatin-resistant A549R cells, but also could inhibit the proliferation of 3D multicellular tumor spheroids. More importantly, Ir-NPX could induce severe mitochondrial injury and endoplasmic reticulum (ER) stress, lead to elevated intracellular free Ca²⁺ levels, and ultimately trigger the ICD effect in A549R cells. This approach of integrating bioactive molecules with metal species paved the way for the development of novel metal-based drugs for combined chemo-immunotherapy in cancer treatment.