• • ATZn nanoparticles co-deliver TDO inhibitor and acetaminophen, achieving dual blockade of kynurenine pathway at TDO and HAAO nodes, reducing both Kyn and QA production; statistical significance of immune modulation reached p < 0.01 and p < 0.0001 in flow cytometry analyses.
• • QA suppression via HAAO inhibition reduced M2 macrophage polarization (CD45+ F4/80+ CD86− CD206+) and increased M1 macrophages (CD45+ F4/80+ CD86+ CD206−), with differences significant at p < 0.01, indicating a shift toward pro-inflammatory tumor microenvironment.
• • Kyn inhibition and Zn2+ supplementation increased CD8+ T cell infiltration (CD45+ CD3+ CD4− CD8+) and reduced Treg cells (CD45+ CD3+ CD4+ CD8− Foxp3+), with statistical significance at p < 0.0001, correlating with enhanced antitumor cytotoxicity.
• • The acid-responsive design of ATZn enables targeted release in tumor microenvironment, potentially improving therapeutic index and reducing systemic toxicity compared to free drug combinations, as evidenced by effective immune modulation at tolerated doses.