A pH-sensitive polyprodrug nanoreactor to alleviate immunosuppression by programmed tumor-specific lactate depletion and indoleamine 2,3-dioxygenase 1 inhibition.

Although lactate oxidase (LOX)-based nanoplatforms have received considerable attention in modulating the immunosuppressive tumor microenvironment (TME), their clinical translation is hampered as most nanoenzymes rely on intratumoral injection to ensure tumor-specific lactate exhaustion and to avoid potential side effects. Here we report a LOX-loaded polyprodrug nanoreactor with tunable membrane permeability in response to the acidic tumor microenvironment for selective lactate exhaustion in tumors after intravenous administration. Additionally, LOX-catalyzed lactate oxidation can generate abundant H2O2 to promote the release of NLG919 from the polyprodrug nanoreactors, thus reprogramming the immunosuppressive TME via cooperative lactate depletion and NLG919-mediated indoleamine 2,3-dioxygenase 1 inhibition in tumors. As a result, the intelligent polyprodrug nanoreactors can elicit intense antitumor immunity after intravenous administration, especially in combination with PD-L1 checkpoint blockade, thereby realizing effective and long-lasting suppression of primary and metastatic tumors without the concern of systemic toxicity.