Shao Changxin, Qiao Shiqi, Meng Yizi, He Tianxiao, Cui Lifeng, He Jin
Department of Obstetrics, Obstetrics and Gynecology Center, The First Hospital of Jilin University, Changchun, Jilin, China.
The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China.
FASEB J. 2025 Sep 15;39(17):e71023. doi: 10.1096/fj.202500974R.
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.
肿瘤相关巨噬细胞（TAMs）在免疫抑制性肿瘤微环境（TME）中起着至关重要的作用，近年来在癌症治疗中受到广泛关注。然而，同时诱导TAM重极化并增强其对癌细胞的吞噬能力仍然是一项重大挑战。铁死亡因其对肿瘤细胞的致死作用而受到广泛关注，但其在TAMs中的作用及其对肿瘤进展的影响尚未明确。在此，构建了基于M2型肿瘤相关巨噬细胞（M2-TAMs）靶向纳米气泡（NBs）的（M2-pep@SF-NBs），用于超声控制递送铁死亡激动剂索拉非尼（SF），以增强巨噬细胞介导的癌症免疫治疗。SF导致M2发生铁死亡并调节其向M1重极化，促进肿瘤内（细胞毒性T淋巴细胞）CTL浸润，从而激活TME，显著抑制肿瘤生长。此外，超声（US）诱导的巨噬细胞铁死亡显著提高了抗PD-1（aPD-1）疗法对肿瘤的疗效。构建M2-pep@SF-NBs以特异性靶向巨噬细胞铁死亡和重极化，将这种治疗与aPD-1联合使用可发挥显著的抗肿瘤疗效。这些发现为深入探索TAMs中铁死亡的激活及其浸润和功能的调节奠定了基础，旨在提高肿瘤预防和治疗效果。
