Bioengineered Stroma‐Camouflaged Nanovesicles Disrupt the IDO1/CD276 Immunosuppressive Circuit to Reinvigorate Antitumor Immunity

ABSTRACT

The cooperative upregulation of IDO1 and the immune checkpoint CD276 in solid tumors establishes a dual immunosuppressive circuit that depletes tryptophan, accumulates kynurenines, and silences T‐cells. We engineered fibroblast‐mimetic nanovesicles (AM@UIO‐BMS/DOX) that uniquely integrate stromal‐camouflaged tumor accumulation, CD276 checkpoint blockade, and co‐delivery of doxorubicin with the clinical IDO1 inhibitor BMS‐986205. The fibroblast‐derived membrane coating promotes accumulation in fibroblast‐rich tumor regions, while surface‐anchored anti‐CD276 scFv enables precision tumor specific targeting and concurrent checkpoint neutralization. Within the tumor microenvironment, doxorubicin elicits immunogenic cell death, and BMS‐986205 metabolically recalibrates the tryptophan–kynurenine equilibrium, relieving the metabolic suppression that otherwise blunts T‐cell priming. In syngeneic tumor models, this bioengineered platform profoundly remodeled the immune microenvironment, as evidenced by a tripartite shift: enhanced dendritic cell maturation and cross‐presentation, expansion of Granzyme B ⁺ cytotoxic CD8 ⁺ T lymphocytes, and selective depletion of CD25 ⁺ FoxP3 ⁺ regulatory T cells. This concerted action effectively converted immunologically “cold” tumors into an inflamed phenotype, overcoming intrinsic chemoresistance and adaptive immune evasion. Collectively, our findings establish that bioengineered stroma‐camouflaged nanovesicles disrupt the dual IDO1/CD276 immunosuppressive circuit, enhancing antitumor immunity and offering a promising strategy to surmount chemo‐immunotherapy resistance in advanced solid tumors.