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

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.