Metalloimmunotherapy with Rhodium and Ruthenium Complexes: Targeting Tumor‐Associated Macrophages

Abstract

Tumor associated macrophages (TAMs) suppress the cancer immune response and are a key target for immunotherapy. The effects of ruthenium and rhodium complexes on TAMs have not been well characterized. To address this gap in the field, a panel of 22 dirhodium and ruthenium complexes were screened against three subtypes of macrophages, triple-negative breast cancer and normal breast tissue cells. Experiments were carried out in 2D and biomimetic 3D co-culture experiments with and without irradiation with blue light. Leads were identified with cell-type-specific toxicity toward macrophage subtypes, cancer cells, or both. Experiments with 3D spheroids revealed complexes that sensitized the tumor models to the chemotherapeutic doxorubicin. Cell surface exposure of calreticulin, a known facilitator of immunogenic cell death (ICD), was increased upon treatment, along with a concomitant reduction in the M2-subtype classifier arginase. Our findings lay a strong foundation for the future development of rutheniumand rhodium-based chemotherapies targeting TAMs.

Controversial Role of Transferrin in the Transport of Ruthenium Anticancer Drugs

“…These applications rely on the ability of metal complexes with lipophilic organic ligands to enter cells rapidly via passive diffusion and cause high cytotoxicity, while their decomposition products, such as metal–protein complexes, are much less toxic and can have beneficial effects [ 14 , 76 ]. Potential beneficial effects of Ru(III)–protein adducts [ 14 ] can include antimetastatic [ 16 , 77 ], immunomodulatory [ 8 , 9 , 19 ], and antimicrobial [ 78 ] activities [ 14 ]. The development of these novel applications is particularly attractive for KP1019 and other anticancer metal complexes that have passed extensive animal testing but failed in human clinical trials [ 1 ] because of unfavorable pharmacokinetic properties for the traditional intravenous chemotherapy [ 14 ].…”

“…Unique photophysical properties of Ru can lead to its applications in light-activated anticancer drugs and in photodynamic therapy [ 7 ]. Some Ru complexes showed immunogenic properties that are particularly promising for cancer immunotherapy [ 8 , 9 ].…”

Ruthenium-based antitumor drugs and delivery systems from monotherapy to combination therapy

“…These DAMPs enhance antigen presentation in dendritic cells (DCS) and subsequently activate infiltrating T cells in the tumor immune microenvironment 308 . Ruthenium complexes (such as KP1339) can cause immunogenic cell death in chemotherapy, photothermal therapy and photodynamic therapy 309 Another study screened a mononuclear ruthenium complex 312 , which selectively killed immunosuppressive M2 macrophages, sensitized macrophage/cancer cell 3D co-cultured spheres to chemotherapeutic drugs, and increased cell surface exposure to calreticulin.…”

“…Another study screened a mononuclear ruthenium complex 312 which selectively killed immunosuppressive M2 macrophages, sensitized macrophage/cancer cell 3D co-cultured spheres to chemotherapeutic drugs, and increased cell surface exposure to calreticulin.…”

Chromium Nanoparticles Improve Macrophage and T Cell Infiltration for Cancer Immunotherapy

“…Besides the commonly used immune-adjuvants, previous studies have revealed that nutritional metal ions play key roles in activating host immunity, , for example Na + , Ca 2+ , and K + for inflammatory response, − Fe 2+/3+ , Cu 2+ , and Mn 2+ for host–pathogen defense, − Mg 2+ , Ca 2+ , and K + for T cell effector function modulation, − and Zn 2+ , Ca 2+ , and Mn 2+ for innate immune activation. ,, Nanomedicine-based metalloimmunotherapy may be a good platform for synergizing cancer immunotherapy in preclinical and clinical trials. − Interestingly, after screening a series of metal ions for improving antitumor immunity, we found that the trivalent chromium ions (Cr 3+ ) had potential in cancer immunotherapy by increasing the infiltration of immune cells into a solid tumor, and this will be the first report exploring the mechanism of Cr-based metalloimmunotherapy. Cr is an essential nutrient for mammalian organisms and improves the symptoms of insulin resistance, type 2 diabetes, and innate and adaptive immune response .…”