Cancer metastasis is a serious concern and a major reason for treatment failure. Herein, we have reported the development of an effective and safe nanotherapeutic strategy that can eradicate primary tumors, inhibit metastasizing to lung, and control the metastasis and growth of distant tumors. Briefly, ferrimagnetic vortex-domain iron oxide nanoring (FVIO)-mediated mild magnetic hyperthermia caused calreticulin (CRT) expression on the 4T1 breast cancer cells. The CRT expression transmitted an "eat-me" signal and promoted phagocytic uptake of cancer cells by the immune system to induce an efficient immunogenic cell death, further leading to the macrophage polarization. This mild thermotherapy promoted 88% increase of CD8 + cytotoxic T lymphocyte infiltration in distant tumors and triggered immunotherapy by effectively sensitizing tumors to the PD-L1 checkpoint blockade. The percentage of CD8 + cytotoxic T lymphocytes can be further increased from 55.4% to 64.5% after combining with PD-L1 blockade. Moreover, the combination treatment also inhibited the immunosuppressive response of the tumor, evidenced by significant down-regulation of myeloid-derived suppressor cells (MDSCs). Our results revealed that the FVIO-mediated mild magnetic hyperthermia can activate the host immune systems and efficiently cooperate with PD-L1 blockade to inhibit the potential metastatic spreading as well as the growth of distant tumors.

In this study, a magnetothermodynamic (MTD) therapy is introduced as an efficient systemic cancer treatment, by combining the magnetothermal effect and the reactive oxygen species (ROS)-related immunologic effect, in order to overcome the obstacle of limited therapeutic efficacy in current magnetothermal therapy (MTT). This approach was achieved by the development of an elaborate ferrimagnetic vortex-domain iron oxide nanoring and graphene oxide (FVIOs-GO) hybrid nanoparticle as the efficient MTD agent. Such a FVIOs-GO nanoplatform was shown to have high thermal conversion efficiency, and it was further proved to generate a significantly amplified ROS level under an alternating magnetic field (AMF). Both in vitro and in vivo results revealed that amplified ROS generation was the dominant factor in provoking a strong immune response at a physiological tolerable temperature below 40 °C in a hypoxic tumor microenvironment. This was supported by the exposure of calreticulin (CRT) on 83% of the 4T1 breast cancer cell surface, direct promotion of macrophage polarization to pro-inflammatory M1 phenotypes, and further elevation of tumor-infiltrating T lymphocytes. As a result of the dual action of magnetothermal effect and ROS-related immunologic effect, impressive in vivo systemic therapeutic efficacy was attained at a low dosage of 3 mg Fe/kg with two AMF treatments, as compared to that of MTT (high dosage of 6–18 mg/kg under four to eight AMF treatments). The MTD therapy reported here has highlighted the inadequacy of conventional MTT that solely relies on the heating effect of the MNPs. Thus, by employing a ROS-mediated immunologic effect, future cancer magnetotherapies can be designed with greatly improved antitumor capabilities.

Metastasis remains the major cause of death in cancer patients. Thus, there is a need to sensitively detect tumor metastasis, especially ultrasmall metastasis, for early diagnosis and precise treatment of cancer. Herein, an ultrasensitive T1‐weighted magnetic resonance imaging (MRI) contrast agent, UMFNP‐CREKA is reported. By conjugating the ultrasmall manganese ferrite nanoparticles (UMFNPs) with a tumor‐targeting penta‐peptide CREKA (Cys‐Arg‐Glu‐Lys‐Ala), ultrasmall breast cancer metastases are accurately detected. With a behavior similar to neutrophils' immunosurveillance process for eliminating foreign pathogens, UMFNP‐CREKA exhibits a chemotactic “targeting‐activation” capacity. UMFNP‐CREKA is recruited to the margin of tumor metastases by the binding of CREKA with fibrin‐fibronectin complexes, which are abundant around tumors, and then release of manganese ions (Mn2+) to the metastasis in response to pathological parameters (mild acidity and elevated H2O2). The localized release of Mn2+ and its interaction with proteins affects a marked amplification of T1‐weighted magnetic resonance (MR) signals. In vivo T1‐weighted MRI experiments reveal that UMFNP‐CREKA can detect metastases at an unprecedented minimum detection limit of 0.39 mm, which has significantly extended the detection limit of previously reported MRI probe.