Onalespib enhances antitumor immunity through coordinated catalytic and chaperone-dependent regulation of tryptophan metabolism.

Tryptophan metabolism via the kynurenine (Kyn) pathway represents a central mechanism of tumor immune tolerance. Although HSP90 inhibitors have been extensively investigated as anticancer agents, their role in metabolic immune regulation remains incompletely unknown. Here, we identify the HSP90 inhibitor onalespib as a potent suppressor of IDO1-dependent tryptophan metabolism in breast cancer. Mechanistically, onalespib suppresses the tryptophan-kynurenine pathway through coordinated catalytic modulation of IDO1 and interference with HSP90 chaperone-associated regulation of IDO1, accompanied by attenuation of IFN-γ-induced JAK-STAT and NF-κB signaling programs. In vivo, onalespib remodels the tumor immune microenvironment, promotes CD8+ effector T-cell infiltration, and enhances the antitumor efficacy of cisplatin without compromising tolerability. Collectively, these findings define a functional HSP90-IDO1 regulatory axis and provide a mechanistic rationale for combination strategies targeting metabolic immune tolerance.