Hypoxia-adaptive albumin nanosystem modulates lactate metabolism to in situ activate postoperative immunotherapy

Postoperative tumor microenvironment (TME) exemplified by high-intensity focused ultrasound (HIFU), is characterized by severe hypoxia and lactate accumulation, which greatly impairs the body’s antitumor immune responses, resulting in poor overall prognosis. Herein, postoperative environment-specific nanosystem was prepared by encapsulating hypoxia-activated prodrug banoxantrone (AQ4N), IDO1 pathway inhibitor (NLG919), and calcium carbonate (CaCO 3 ) in cross-linked human serum albumin (HSA) to in situ activate HIFU postoperative immunotherapy. After specific accumulation at tumor sites and with photoacoustic imaging guidance for HIFU surgery, the nanosystem rapidly dissociates and releases loaded drugs into the postoperative TME. Hypoxia-adaptive AQ4N is then metabolically activated, mediating the antitumor immunity associated with immunogenic cell death. Meanwhile, NLG919 suppresses the IDO pathway, and CaCO 3 depletes lactate to mitigate the immunosuppressive TME that was worsened following the surgery. As a result, the nanosystem greatly enhances antitumor immune responses after HIFU, showing excellent efficacy against tumor recurrence and metastasis. This offers a successful paradigm for improving the postoperative immunotherapy with immune enhancers for all surgical procedures.