Suppression of lysosome metabolism-meditated GARP/TGF-ß1 complexes specifically depletes regulatory T cells to inhibit breast cancer metastasis.

Regulatory T cells (Tregs) prevent autoimmunity and contribute to cancer progression. They exert contact-dependent inhibition of immune cells through the production of active transforming growth factor-ß1 (TGF-ß1). However, the absence of a specific surface marker makes inhibiting the production of active TGF-ß1 to specifically deplete human Tregs but not other cell types a challenge. TGF-ß1 in an inactive form binds to Tregs membrane protein Glycoprotein A Repetitions Predominant (GARP) and then activates it via an unknown mechanism. Here, we demonstrated that tumour necrosis factor receptor-associated factor 3 interacting protein 3 (TRAF3IP3) in the Treg lysosome is involved in this activation mechanism. Using a novel naphthalenelactam-platinum-based anticancer drug (NPt), we developed a new synergistic effect by suppressing ATP-binding cassette subfamily B member 9 (ABCB9) and TRAF3IP3-mediated divergent lysosomal metabolic programs in tumors and human Tregs to block the production of active GARP/TGF-ß1 for remodeling the tumor microenvironment. Mechanistically, NPt is stored in Treg lysosome to inhibit TRAF3IP3-meditated GARP/TGF-ß1 complex activation to specifically deplete Tregs. In addition, by promoting the expression of ABCB9 in lysosome membrane, NPt inhibits SARA/p-SMAD2/3 through CHRD-induced TGF-ß1 signaling pathway. In addition to expose a previously undefined divergent lysosomal metabolic program-meditated GARP/TGF-ß1 complex blockade by exploring the inherent metabolic plasticity, NPt may serve as a therapeutic tool to boost unrecognized Treg-based immune responses to infection or cancer via a mechanism distinct from traditional platinum drugs and currently available immune-modulatory antibodies.

Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy.

BACKGROUND: Platinum-drugs based chemotherapy in clinic increases the potency of tumor cells to produce M2 macrophages, thus leading to poor anti-metastatic activity and immunosuppression. Lysosome metabolism is critical for cancer cell migration and invasion, but how it promotes antitumor immunity in tumours and macrophages is poorly understood and the underlying mechanisms are elusive. The present study aimed to explore a synergistic strategy to dismantle the immunosuppressive microenvironment of tumours and metallodrugs discovery by using the herent metabolic plasticity. METHODS: Naphplatin was prepared by coordinating an active alkaline moiety to cisplatin, which can regulate the lysosomal functions. Colorectal carcinoma cells were selected to perform the in vivo biological assays. Blood, tumour and spleen tissues were collected and analyzed by flow cytometry to further explore the relationship between anti-tumour activity and immune cells. Transformations of bone marrow derived macrophage (BMDM) and M2-BMDM to the M1 phenotype was confirmed after treatment with naphplatin. The key mechanisms of lysosome-mediated mucolipin-1(Mcoln1) and mitogen-activated protein kinase (MAPK) activation in M2 macrophage polarization have been unveiled. RNA sequencing (RNA-seq) was used to further explore the key mechanism underlying high-mobility group box 1(HMGB1)-mediated Cathepsin L(CTSL)-lysosome function blockade. RESULTS: We demonstrated that naphplatin induces divergent lysosomal metabolic programs and reprograms macrophages in tumor cells to terminate the vicious tumour-associated macrophages (TAMs)-MDSCs-Treg triangle. Mechanistically, macrophages treated with naphplatin cause lysosome metabolic activation by triggering Ca2+ release via Mcoln1, which induces the activation of p38 and nuclear factor-κB (NF-κB) and finally results in polarizing M2 macrophages. In contrast, HMGB1-mediated lysosome metabolic blockade in cancer cells is strongly linked to antitumor effects by promoting cytoplasmic translocation of HMGB1. CONCLUSIONS: This study reveals the crucial strategies of macrophage-based metallodrugs discovery that are able to treat both immunologically "hot" and "cold" cancers. Different from traditional platinum-based antitumour drugs by inhibition of DNAs, we also deliver a strong antitumour strategy by targeting lysosome to induce divergent metabolic programs in macrophages and tumours for cancer immunotherapy.

2-Phenylquinoline-polyamine conjugate (QPC): Interaction with bovine serum albumin (BSA).

A novel 2-phenylquinoline-polyamine conjugate (QPC) was synthesized and characterized, its interaction with bovine serum albumin (BSA) was evaluated using UV-Vis, fluorescence and circular dichroism (CD) spectroscopy. The results showed that QPC caused a whole train of spectral variation, including enhancement of UV-vis absorption and reduction of fluorescence (FL), indicating QPC-BSA complex formed. FL results showed that the type of FL quenching waslarge static quenching, which was also accompanied with a process of dynamic quenching. Binding constants, thermodynamic parameters and docking results showed that the interaction between QPC and BSA was basically a Van der Waals, hydrogen bond and hydrophobic interaction. Synchronous and 3D-FL analysis revealed that QPC resulted in unapparent conformational alteration of BSA. The docking study suggested QPC was situated at the binding sites II of BSA, and 2-phenylquinoline moiety contributed to the hydrophobic interaction. The results of molecular dynamics revealed QPC altered the conformation of BSA, which showed that the inconsistency between experimental data and theoretical calculation results may be due to the instability of the compound.

The role of Platinum(IV)-based antitumor drugs and the anticancer immune response in medicinal inorganic chemistry. A systematic review from 2017 to 2022.

Platinum-based antitumor drugs have been used in many types of tumors due to its broad antitumor spectrum in clinic. Encouraged by the cisplatin's (CDDP) worldwide success in cancer chemotherapy, the research in platinum-based antitumor drugs has evolved from traditional platinum drug to multi-ligand and multifunctional platinum prodrugs over half a century. With the rapid development of metal drugs and the anticancer immune response, challenges and opportunities in platinum drug research have been shifted from traditional platinum-based drugs to platinum-based hybrids and the direction of development is tending toward photodynamic therapy, nano-delivery therapy, drug combination, targeted therapy, diagnostic therapy, immune-combination therapy and tumor stem cell therapy. In this review, we first exhaustively overviewed the role of platinum-based antitumor prodrugs and the anticancer immune response in medicinal inorganic chemistry based on the special nanomaterials, the modification of specific ligands, and the multiple functions obtained that are beneficial for tumor therapy in the last five years. We also categorized them according to drug potency and function. There hasn't been a comprehensive evaluation of precursor platinum drugs in prior articles. And a multifarious approach to distinguish and detail the variety of alterations of platinum-based precursors in various valence states also hasn't been summarized. In addition, this review points out the main problems at the interface of chemistry, biology, and medicine from their action mechanisms for current platinum drug development, and provides up-to-date potential strategies from drug design perspectives to circumvent those drawbacks. And a promising idea is also enlightened for researchers in the development and discovery of platinum prodrugs.