Nanoparticle‐Based MRI‐Guided Tumor Microenvironment Heating via the Synergistic Effect of Ferroptosis and Inhibition of TGF‐β Signaling

Abstract

Although induction of ferroptosis and inhibition of transforming growth factor‐β (TGF‐β) signaling are both effective ways to reform the tumor microenvironment (TME) and render low‐immunogenic tumors responsive to immune checkpoint inhibitor therapy, dose‐limiting side effects remain major obstacles hindering their clinical application. Herein, novel sorafenib and anti‐TGF‐β antibody loaded Fe3O4/Gd2O3 hybrid nanoparticles with conjugation of arginine‐glycine‐aspartic dimer (FeGd‐HN@Sorafenib@TGF‐β‐antibody@RGD2, FG‐STR) are developed. Sorafenib significantly enhances FeGd‐HN‐triggered ferroptosis and improves maturation and phagocytosis of dendritic cells (DCs) by inducing damage‐associated molecular patterns released from ferroptotic cancer cells, while the anti‐TGF‐β antibody further synergizes with enhanced ferroptosis to promote DC maturation and the recruitment of CD8+ T cells, thus heating the TME. Moreover, the incorporation of RGD2 facilitates the uptake of the FG‐STR in tumor cells which lead to a significant dosage reduction of both sorafenib and anti‐TGF‐β antibody to avoid dose‐limiting toxicities. Finally, in vitro and in vivo experiments show that FG‐STR has significantly superior intrinsic magnetic resonance imaging (MRI) capability than that of Gadovist, effectively inhibits tumor growth and lung metastasis, and increases the efficacy of anti‐programmed cell death‐1 treatment. Taken together, this study provides a promising strategy for new advanced MRI‐guided TME heating therapies.

The crosstalk between ferroptosis and anti‐tumor immunity in the tumor microenvironment: molecular mechanisms and therapeutic controversy

“…The radiated tumor cell–released microparticles (RT‐MP) released by irradiated lung carcinoma cells can cause ferroptosis of tumor cells, and the release of extracellular CRT and ATP in the medium increased after treatment with RT‐MP [ 76 ]. Similarly, in recent studies investigating the use of nanomedicines to induce ferroptosis for cancer treatment, a few findings have highlighted the release of DAMPs by drug‐induced ferroptotic cancer cells [ 52 , 54 , 60 , 62 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ], and in several studies, the promotion of DC maturation has also been reported [ 54 , 82 , 83 , 84 , 85 ]. In addition to the most well‐known DAMPs, namely HMGB1, ATP and CRT, Liu et al.…”

“…Furthermore, recent studies, particularly those focused on nanoparticle‐based approaches, have provided ample evidence for the immunomodulatory effects of inducing ferroptosis in cancer cells. For example, many studies have demonstrated that ferroptotic cancer cells promote immune cell infiltration or activation, thereby improving the immunosuppressive TME [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 62 , 79 , 84 , 85 , 118 , 119 , 120 , 121 , 122 ]. Several studies have also shown that inducing ferroptosis in cancer cells significantly enhances the efficacy of immunotherapy [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ].…”

“…For example, many studies have demonstrated that ferroptotic cancer cells promote immune cell infiltration or activation, thereby improving the immunosuppressive TME [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 62 , 79 , 84 , 85 , 118 , 119 , 120 , 121 , 122 ]. Several studies have also shown that inducing ferroptosis in cancer cells significantly enhances the efficacy of immunotherapy [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. Certain studies have even reported that inducing ferroptosis in cancer cells can lead to durable immune memory in vivo, directly eliminating rechallenged cancer cells and preventing tumor formation [ 56 , 121 ].…”

“…Moreover, many studies have not meticulously ruled out the direct effects of the employed drugs on anti‐tumor immunity. Some drugs may harbor immunostimulatory elements that can independently influence the tumor immune response [ 54 , 78 ]. Therefore, it is challenging to ascertain whether the observed alterations in anti‐tumor immunity are solely induced by ferroptotic cancer cells or influenced by additional factors like the drugs employed.…”

“…Recent studies have suggested the potential of integrating ferroptosis‐targeted therapy with immunotherapy for tumor treatment [ 46 , 47 ]. Several studies have indicated a cooperative effect between ferroptosis induction and ICIs [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ], suggesting a promising future for this combined treatment approach. However, further investigation has shown that ferroptosis has a complex impact on anti‐tumor immunity, affecting the feasibility of such a combination strategy.…”