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UTND Effect Mediates Macrophage Ferroptosis and Promotes Immune Microenvironment Remodeling of Ovarian Cancer
Changxin Shao1, Shiqi Qiao2, Yizi Meng1
1Department of Obstetrics, Obstetrics and Gynecology Center, The First Hospital of Jilin University, Changchun, Jilin, China.
Abstract:
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.
Insights
This study developed targeted nanobubbles to deliver sorafenib, inducing ferroptosis in M2 tumor-associated macrophages (TAMs). This approach repolarizes TAMs, enhances anti-tumor immunity, and improves cancer immunotherapy effectiveness.
Area of Science:
- Oncology
- Immunology
- Nanomedicine
Background:
- Tumor-associated macrophages (TAMs) create an immunosuppressive tumor microenvironment (TME), hindering cancer treatment.
- Repolarizing TAMs and enhancing their phagocytic activity remain significant challenges in cancer therapy.
- The role of ferroptosis in TAMs and its impact on tumor progression require further definition.
Purpose of the Study:
- To develop M2-TAM-targeted nanobubbles for ultrasound-controlled delivery of sorafenib (SF).
- To investigate the potential of SF-loaded nanobubbles to induce ferroptosis and repolarize M2-TAMs for enhanced cancer immunotherapy.
- To evaluate the synergistic anti-tumor efficacy of M2-TAM-targeted ferroptosis induction combined with anti-PD-1 therapy.
Main Methods:
- Construction of M2-TAM-targeted nanobubbles loaded with sorafenib (M2-pep@SF-NBs).
- Utilized ultrasound (US) for controlled drug release and induction of macrophage ferroptosis.
- Assessed the effects of M2-pep@SF-NBs on TAM repolarization, cytotoxic T lymphocyte (CTL) infiltration, and tumor growth inhibition.
- Evaluated the combination therapy of M2-pep@SF-NBs and anti-PD-1 (aPD-1) in a tumor model.
Main Results:
- SF-loaded nanobubbles successfully induced ferroptosis in M2-TAMs and promoted their repolarization to M1 phenotype.
- Ultrasound-triggered ferroptosis enhanced intratumoral CTL infiltration and activated the TME, significantly inhibiting tumor growth.
- Combination therapy with M2-pep@SF-NBs and aPD-1 demonstrated significant synergistic anti-tumor efficacy.
Conclusions:
- M2-TAM-targeted nanobubbles offer a promising strategy for ultrasound-controlled ferroptosis induction and TAM repolarization.
- This approach enhances macrophage-mediated cancer immunotherapy and improves the effectiveness of anti-PD-1 therapy.
- Targeting TAM ferroptosis and function holds potential for advancing cancer prevention and therapeutic outcomes.
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