Cancer cells require plentiful energy to keep up with the increasing demands for proliferation and division [1], thus, mitochondrial bioenergy is critical in the incidence and progression of cancer [2]. For cancer therapy, strategies such as disrupting the electron transport chain (ETC), impeding mitochondrial autophagy, and generating mitochondrial DNA damage have been rapidly developed [3], [4], [5]. However, the anticancer efficacy of these promising strategies remains unsatisfactory, owing to the demands on oxidative phosphorylation (OXPHOS) and glycolysis to supply cancer cell energy [6], [7], [8], [9], [10]. Even though one pathway of energy metabolism is inhibited, the other will be activated to compensate for the energy loss. Thus, dual inhibition of OXPHOS and glycolysis would be an effective strategy to enhance the cancer therapy, with the disruption of metabolic adaption to cut off the energy supply of the cancer cells.

Metal complexes with mitochondria-targeting ability, such as those of Pt, Au, Ru, or Ir, have become an attractive class of complexes for cancer therapy with a diverse mechanism of action (MoAs) [11], [12], [13], [14]. Wang et al. developed a triphenylphosphonium-modified terpyridine Pt(II) complex (TTP) exerting strong inhibition to both mitochondrial and glycolytic bioenergetics, thus inducing cell autophagy [15]. Chao group prepared a mitochondria-localized Ir(III) photosensitizer, which could produce singlet oxygen and superoxide anion radicals, and evoke the ferroptosis of the cell death [16]. Our group previously designed a novel rhein-based cyclometalated Ir(III) complex, Ir-Rhein, which could also accumulate in mitochondria, effectively inhibit metabolic adaptations, and overcome metallodrug resistance through mitophagy [17]. Even though various mitochondria targeting metal complexes have been reported, it remains a great challenge to simultaneously inhibit the dual of the OXPHOS and glycolysis and activate multiple synergistic cell death pathways, evenly realize the suppression of the cancer cell progression.

Vitamin E analogues, with α-tocopheryl succinate (α-TOS) as a prototype complex, have exhibited the capacity to selectively trigger mitochondrial apoptosis in tumor cells [18]. Previous mechanism studies revealed that α-TOS localized to mitochondria due to interactions with the ubiquinone-binding sites of respiratory chain complex II, subsequently inducing reactive oxygen species (ROS) elevation and cell death [19]. For example, the Lippard group reported two α-TOS-decorated Pt(IV) complexes significantly facilitate the cellular uptake of Pt(IV), resulting in the DNA damages and mitochondria damages simultaneously [20]. However, the potential to influence both the mitochondrial metabolism pathways of α-TOS was still unrevealed.

Herein, we combined α-TOS and cyclometalated Ir(III) complex to form mitochondria targeting complexes Ir1, Ir2 to investigate the potent to dual inhibit of OXPHOS and glycolysis (Scheme 1). The α-TOS-free complexes Ir1a and Ir2a were also synthesized as the control. The introduction of α-TOS fragment effectively enhanced the lipid solubility and facilitated the mitochondrial targeting. Complex Ir2 exhibited the highest cytotoxicity against the human cancer cells and induced significant ROS production, and decreased mitochondrial membrane potential. Furthermore, Ir2 strongly inhibited both mitochondrial and glycolytic bioenergetics, resulting in a significant blockage of the ATP production of cancer cells, ultimately evoking the cell death with a synergistic mode of apoptosis and autophagy. The promising anti-tumor capacity of Ir2 was also observed in the 3D multicellular tumor spheroids model. This study not only presents a successful anti-cancer metal complex therapeutic agent with dual suppression of OXPHOS and glycolysis, but also further underscores the efficacy of mitochondria targeting strategies in cancer treatment.