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 in vivo 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.