UTND Effect Mediates Macrophage Ferroptosis and Promotes Immune Microenvironment Remodeling of Ovarian Cancer.

Tumor-associated macrophages (TAMs) act as a vital player in the immunosuppressive tumor microenvironment (TME) and have received widespread attention in the treatment of cancer in recent times. Nevertheless, simultaneously inducing TAM repolarization and strengthening their phagocytic ability on cancer cells is still a significant challenge. Ferroptosis has received widespread attention due to its lethal effects on tumor cells, but its role in TAMs and its impact on tumor progression have not yet been defined. Here, M2-type tumor-associated macrophages (M2-TAMs) targeted nanobubbles (NBs)-based (M2-pep@SF-NBs) were constructed for ultrasound-controlled delivery of the ferroptosis agonist sorafenib (SF) to enhance macrophage-mediated cancer immunotherapy. SF causes ferroptosis of M2 and regulates repolarization to M1 and promotes intratumoral (cytotoxic T lymphocyte) CTL infiltration, leading to activation of the TME that significantly inhibits tumor growth. Additionally, ultrasound (US)-induced macrophage ferroptosis notably improved the effectiveness of anti-PD-1 (aPD-1) therapy against tumors. M2-pep@SF-NBs were constructed to specifically target macrophage ferroptosis and repolarization, and combining this treatment with aPD-1 exerted significant anti-tumor efficacy. These findings lay the groundwork for deeper exploration of ferroptosis activation in TAMs and the regulation of their infiltration and function, aiming to enhance tumor prevention and therapeutic outcomes.