Engineering of Sono-Activatable Immunogels for Immunometabolism Disorder Normalization Therapy of Breast Cancer

Sonodynamic therapy (SDT) represents a promising approach for localized immunotherapy of solid tumors, yet its clinical translation is limited by therapy stress-induced adaptive immune resistance. Here, we demonstrate that SDT initially elicits antitumor immune response while consequently induces immunometabolic dysregulation via the interferon-gamma (IFN-γ)/indoleamine-2,3-dioxygenase-1 (IDO-1) axis to promote regulatory T cell (Treg) expansion. To counteract this negative regulation mechanism, we develop a sono-activatable prodrug (MB-MT) by conjugating the sonosensitizer methylene blue (MB) with the IDO-1 inhibitor 1-methyltryptophan (MT) via an ultrasound-labile urea bond. MB-MT is further incorporated into a thermosensitive hydrogel to yield an ultrasound-responsive immunogel that enables spatiotemporally confined SDT while locally suppressing IDO-1-mediated immune suppression. The combination of the immunogel with SDT treatment markedly normalizes the immunosuppressive tumor microenvironment to inhibit primary and metastatic tumor growth, and prevent postoperative recurrence in multiple synergistic mouse models of triple negative breast cancer (TNBC). This work presents a practical strategy for localized immunotherapy of TNBC by spatiotemporally confined normalization of immunometabolism disorder.