Developing\na Rhodium(III) Complex to Reprogram the\nTumor Immune and Metabolic Microenvironments: Overcoming Multidrug\nResistance and Metastasis in Non-Small Cell Lung Cancer

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