Ferroptosis is a form of regulatory cell death (RCD) evoked by lipid peroxides (LPO) [1], [2], [3], [4]. Unlike other RCD modalities such as apoptosis and necrosis, ferroptosis is not regulated by apoptosis effectors or necrosis inducers, showing great potential in cancer therapy [5,6]. The key chemical steps of ferroptosis include reactive oxygen species (ROS) production, LPO accumulation and glutathione (GSH) depletion [7]. On the one hand, iron ions increase the level of intracellular ROS by triggering the Fenton reaction, causing oxidative damage and contributing to the accumulation of LPO [8]. On the other hand, GSH, as the most important antioxidant, is involved in the maintenance of intracellular redox homeostasis and catalyzes the reduction of LPO as one of the co-substrates of glutathione peroxidase 4 (GPX4). The consumption of GSH can disrupt the redox balance and effectively inhibit GPX4 expression [9,10]. However, the complex tumor microenvironment (TME) not only has an inhomogeneous vascular network, dense tumor tissues, and high interstitial pressure, which makes it difficult for nanoparticles to reach the tumor cells and accumulate effectively at the tumor site [11,12]. It also promotes immune evasion and immunosuppression, which is conducive to the migration and invasion of cancer cells [13]. At the same time, the long-term retention of nanomaterials in the organism is prone to cause damage to the cells, leading to chronic inflammatory reactions and affecting the immune system function of the organism [14,15]. Therefore, in the process of tumor ferroptosis induced by nanoparticles, how to enhance tumor-targeted accumulation, improve the effect of anti-tumor therapy, and promote the metabolic capacity in vivo are the problems and challenges we need to face.

To achieve the specific tumor-targeting effect of nanoparticles and enhance tissue penetration and metabolic capacity in vivo, various drug delivery systems have been explored and are extensively used in cancer therapy [16], [17], [18]. Hyaluronic acid (HA) has good water solubility and biosafety that can target overexpressed CD44 on tumor cell membranes [19,20]. It can be degraded by hyaluronidase (HAase) contained in the TME, releasing the encapsulated nanomaterials or drugs [21]. In addition, studies have shown that ultra-small nanoparticles can achieve effective penetration of tumor tissues without additional modifications, improving their ability to aggregate at the tumor site [22,23]. It can also be metabolically cleared over a while, reducing the side effects of nanomaterials [24,25].

Reprogramming the immunosuppressive TME to inhibit the migration of cancer cells to achieve better anti-tumor immunotherapy effect is a feasible scheme [26], [27], [28]. The immunosuppressive TME disables the host's immune system and has a significant negative impact on the efficacy of most cancer therapies [29]. Overexpression of indoleamine 2,3-dioxygenase (IDO) is a common vehicle used by a range of tumor cells to manifest immunosuppressive features. It induces cell cycle arrest to acquire peripheral tolerance and effector T cell death through catalyzing the transformation of tryptophan (Trp) into kynuridine (Kyn), while activating immunosuppressive Tregs [30]. NLG919, a highly selective IDO inhibitor, can reduce Kyn accumulation, inhibit the differentiation of Tregs, and reverse the immunosuppressive TME to enhance cancer treatment [31].

Herein, we constructed a nanocomplex with tumor-specific targeting and TME response to enhance the therapeutic effect of ferroptosis. Ultra-small nanoparticles MnFe2O4@NaGdF4 (MG) with Janus structure were synthesized by a one-pot method. Subsequently, the MnFe2O4@NaGdF4@NLG919@HA (MGNH) nanocomplex was constructed by loading NLG919 and HA to effectively induce ferroptosis activation for synergistic tumor immunotherapy (Scheme 1). After targeting CD44 receptors on the tumor cell membranes, HA could be broken down by the overexpressed HAase in TME to achieve precise delivery of MG and NLG919 to tumor cells. MG with T1/T2 dual-mode imaging ability not only achieved photothermal therapy (PTT) of tumors under 808 nm laser irradiation, but also catalyzed endogenous H2O2 to produce ROS and consumed GSH overexpressed in the TME, effectively promoted LPO accumulation and inhibited GPX4 expression to induce ferroptosis. Meanwhile, NLG919, as a highly selective blocking inhibitor of the IDO-mediated Trp/Kyn immune escape pathway, could enhance the function of effector T cells by inhibiting Tregs differentiation, and thus realize immunotherapy together with Mn2+-activated cGAS-STING pathway.