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J Med Chem ; 67(16): 13778-13787, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39134504

RESUMO

Metal-based chemoimmunotherapy has recently garnered significant attention for its capacity to stimulate tumor-specific immunity beyond direct cytotoxic effects. Such effects are usually caused by ICD via the activation of DAMP signals. However, metal complexes that can elicit antitumor immune responses other than ICD have not yet been described. Herein, we report that a rhodium complex (Rh-1) triggers potent antitumor immune responses by downregulating Wnt/ß-catenin signaling with subsequent activation of T lymphocyte infiltration to the tumor site. The results of mechanistic experiments suggest that ROS accumulation following Rh-1 treatment is a critical trigger of a decrease in ß-catenin and enhanced secretion of CCL4, a key mediator of T cell infiltration. Through these properties, Rh-1 exerts a synergistic effect in combination with PD-1 inhibitors against tumor growth in vivo. Taken together, our work describes a promising metal-based antitumor agent with a noncanonical mode of action to sensitize tumor tissues to ICB therapy.


Assuntos
Antineoplásicos , Ródio , Via de Sinalização Wnt , Ródio/química , Ródio/farmacologia , Animais , Via de Sinalização Wnt/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Humanos , Camundongos , beta Catenina/metabolismo , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/uso terapêutico , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BL
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