Developing a Rhodium(III) Complex to Reprogram the Tumor Immune and Metabolic Microenvironments: Overcoming Multidrug Resistance and Metastasis in Non-Small Cell Lung Cancer

To effectively inhibit the growth and metastasis of non-small cell lung cancer (NSCLC) and overcome its multidrug resistance (MDR), we designed and synthesized a series of rhodium (Rh, III) 2-benzoylpyridine thiosemicarbazone complexes. Through studying their structure-activity relationships, we identified the Rh(III) complex (Rh4) with excellent cytotoxicity against multidrug-resistant lung cancer cells (A549/ADR cells). Additionally, we successfully constructed an apoferritin (AFt) nanoparticle (NP) delivery system (AFt-Rh4 NPs). Importantly, AFt-Rh4 NPs not only exhibited excellent antitumor and antimetastatic capabilities against multidrug-resistant NSCLC <i>in vivo</i> but also demonstrated enhanced targeting ability and reduced systemic toxicity and adverse effects. Furthermore, we confirmed and elucidated the mechanisms by which Rh4/AFt-Rh4 NPs inhibit tumor metastasis and reverse MDR in NSCLC. This was achieved by reprogramming the immune and metabolic tumor microenvironments through induction of immunogenic cell death and inhibition of dual-energy metabolism.