Zihan Zhao

Cancer immunotherapy holds great promise but is often limited by tumor immune evasion via major histocompatibility complex class I (MHC-I) downregulation. To overcome this, we rationally designed a trinuclear ruthenium-platinum complex (TriRuPt) that leverages metal-enhanced photooxidation and exhibits light-induced nuclear translocation. As a photosensitizer in photodynamic therapy (PDT), TriRuPt generates reactive oxygen species to disrupt cellular homeostasis and triggers dual immunomodulatory effects: (i) MHC-I upregulation, enhancing T cell recognition and activation, and (ii) induction of immunogenic cell death (ICD), promoting dendritic cell-mediated antigen presentation and amplifying antitumor immunity. Furthermore, TriRuPt-mediated PDT synergizes with immune checkpoint inhibitors, significantly suppressing tumor growth in vivo, reprogramming the tumor microenvironment, and enhancing adaptive immune responses. This study establishes a metal-based dual immunomodulatory strategy to potentiate immune checkpoint blockade therapy and reveals an underexplored immunoregulatory property of transition metal complexes, providing a promising strategy to overcome tumor immune evasion and resistance in cancer immunotherapy.

Single-cell RNA sequencing (scRNA-seq) using metabolic RNA labeling enables detailed analysis of dynamic gene expression within single cells. However, most studies are limited to in vitro settings, restricting the exploration of in vivo transcriptomic dynamics. To address this, we developed scDyna-seq, a time-resolved scRNA-seq method for in vivo applications using 4-thiouridine (4sU) labeling. scDyna-seq efficiently captures nascent RNA, allowing for precise tracking of gene expression in both in vitro and in vivo contexts, including crossing the blood-brain and blood-fetal barriers. It is also compatible with other single-cell multiomics approaches. In a mouse bladder cancer model, scDyna-seq revealed that cisplatin (cis-diaminodichloroplatinum, CDDP) induced significant dynamic changes in tumor-infiltrating lymphocytes, particularly in genes related to costimulation, effector functions, and exhaustion, which were not detected by conventional methods. When coupled with scTCR-seq, scDyna-seq showed increased TCR clonal expansion linked to CDDP-induced immunogenic death and neoantigen production. In conclusion, scDyna-seq offers safe, precise in vivo RNA labeling as well as single-cell analysis, expanding our understanding of cellular dynamics and facilitating research in health and disease.

Cancer cells often upregulate ribosome biogenesis to meet increased protein synthesis demands for rapid proliferation; therefore, targeting ribosome biogenesis has emerged as a promising cancer therapeutic strategy. Herein, we introduce two Pt complexes, ataluren monosubstituted platinum(IV) (SPA, formula: c,c,t,-[Pt(NH3)2Cl2(OH)(C15H8FN2O3)], where C15H8FN2O3 = ataluren) and ataluren bisubstituted platinum(IV) complex (DPA, formula: c,c,t,-[Pt(NH3)2Cl2(C15H8FN2O3)2], where C15H8FN2O3 = ataluren), which effectively suppress ribosome biogenesis by inhibiting 47s pre-RNA expression. Furthermore, SPA and DPA induce nucleolar stress by dispersing nucleolar protein NPM1, ultimately inhibiting protein generation in tumor cells. More importantly, DPA exhibits superior cytotoxicity to various cancer cells and in vivo antitumor efficacy compared to cisplatin, with lower systemic toxicity. Notably, in clinically relevant models, including orthotopic hepatic tumor-bearing mice and patient-derived bladder cancer organoids, DPA outperforms cisplatin significantly, with the added benefit of oral administration, enhancing clinical feasibility. To our knowledge, DPA emerges as the pioneering Pt(IV) agent targeting the ribosome, providing new insights for designing next-generation metal-based therapeutics.

Cancer is a systemic disease continuously monitored and responded to by the human global immune system. Peripheral blood immune cells, integral to this surveillance, exhibit variable phenotypes during tumor progression. Glycosylation, as one of the most prevalent and significant post-translational modifications of proteins, plays a crucial role in immune system recognition and response. Glycan analysis has become a key method for biomarker discovery. LacNAc, a prominent glycosylation modification, regulates immune cell activity and function. Therefore, we applied our previously developed single-cell glycomic multiomics to analyze peripheral blood in cancer patients. This platform utilizes chemoenzymatic labeling with DNA barcodes for detecting and quantifying LacNAc levels at single-cell resolution without altering the transcriptional status of immune cells. For the first time, we systematically integrated single-cell transcriptome, T cell receptor (TCR) repertoire, and glycan epitope LacNAc analyses in tumor-patient-derived peripheral blood. Our integrated analysis reveals that lower-stage bladder cancer patients showed significantly higher levels of LacNAc in peripheral T cells, and peripheral T cells with high levels of cell-surface LacNAc exhibit higher cytotoxicity and TCR clonal expansion. In summary, we identified LacNAc as a potential cell-surface effector marker for peripheral T cells in bladder cancer patients, which enhances our understanding of peripheral immune cells and offers potential advancements in liquid biopsy.

Most of the anticancer compounds synthesized by chemists are primarily evaluated for their direct cytotoxic effects at the cellular level, often overlooking the critical role of the immune system. In this study, we developed a patient‐derived, T‐cell‐retaining tumor organoid model that allows us to evaluate the anticancer efficacy of chemical drugs under the synergistic paradigm of antigen‐specific T‐cell‐dependent killing, which may reveal the missed drug hits in the simple cytotoxic assay. We evaluated clinically approved platinum (Pt) drugs and a custom library of twenty‐eight Pt^IV compounds. We observed low direct cytotoxicity of Pt drugs, but variable synergistic effects in combination with immune checkpoint inhibitors (ICIs). In contrast, the majority of Pt^IV compounds exhibited potent tumor‐killing capabilities. Interestingly, several Pt^IV compounds went beyond direct tumor killing and showed significant immunosynergistic effects with ICIs, outstanding at sub‐micromolar concentrations. Among these, Pt‐19, Pt^IV compounds with cinnamate axial ligands, emerged as the most therapeutically potent, demonstrating pronounced immunosynergistic effects by promoting the release of cytotoxic cytokines, activating immune‐related pathways and enhancing T cell receptor (TCR) clonal expansion. Overall, this initiative marks the first use of patient‐derived immunocompetent tumor organoids to explore and study chemotherapy, advancing their path toward more effective small molecule drug discovery.

Most of the anticancer compounds synthesized by chemists are primarily evaluated for their direct cytotoxic effects at the cellular level, often overlooking the critical role of the immune system. In this study, we developed a patient‐derived, T‐cell‐retaining tumor organoid model that allows us to evaluate the anticancer efficacy of chemical drugs under the synergistic paradigm of antigen‐specific T‐cell‐dependent killing, which may reveal the missed drug hits in the simple cytotoxic assay. We evaluated clinically approved platinum (Pt) drugs and a custom library of twenty‐eight Pt^IV compounds. We observed low direct cytotoxicity of Pt drugs, but variable synergistic effects in combination with immune checkpoint inhibitors (ICIs). In contrast, the majority of Pt^IV compounds exhibited potent tumor‐killing capabilities. Interestingly, several Pt^IV compounds went beyond direct tumor killing and showed significant immunosynergistic effects with ICIs, outstanding at sub‐micromolar concentrations. Among these, Pt‐19, Pt^IV compounds with cinnamate axial ligands, emerged as the most therapeutically potent, demonstrating pronounced immunosynergistic effects by promoting the release of cytotoxic cytokines, activating immune‐related pathways and enhancing T cell receptor (TCR) clonal expansion. Overall, this initiative marks the first use of patient‐derived immunocompetent tumor organoids to explore and study chemotherapy, advancing their path toward more effective small molecule drug discovery.

Most of anticancer compounds synthesized by chemists are primarily evaluated for their direct cytotoxic effects at the cellular level, often overlooking the critical role of the immune system. In this study, we have developed a patient-derived, T-cell-retaining tumor organoid model that allows us to evaluate the anticancer efficacy of chemical drugs under the synergistic paradigm of antigen-specific T-cell-dependent killing, which may reveal the missed drug hits in the simple cytotoxic assay. We evaluated clinically approved platinum (Pt) drugs and a custom library of twenty-eight PtIV compounds in this platform. We observed low direct cytotoxicity of clinically used Pt drugs, but variable synergistic effects in combination with immune checkpoint inhibitors (ICIs) in different patients. In contrast, the majority of PtIV compounds exhibited potent tumor killing capabilities. Interestingly, several PtIV compounds went beyond direct tumor killing and showed significant immunosynergistic effects with ICIs, especially being outstanding at sub-micromolar concentrations. Among these, Pt-19, PtIV compounds with cinnamate axial ligands, emerged as the most therapeutically potent, showing pronounced immunosynergistic effects by promoting the release of cytotoxic cytokines, activating immune-related pathways and enhancing TCR clonal expansion. Overall, this initiative marks the first use of patient-derived immunocompetent tumor organoids to explore and study chemotherapy, advancing their path toward more effective small molecule drug discovery.

FucoID is an intercellular proximity labeling technique for studying cell-cell interactions (CCIs) via fucosyltransferase (FT)–meditated fucosyl-biotinylation, which has been applied to probe antigen-specific dendritic cell (DC)–T cell interactions. In this system, bait cells of interest with cell surface–anchored FT are used to capture the interacting prey cells by transferring a biotin-modified substrate to prey cells. Here, we leveraged FucoID to study CCIs directed by different molecular pairs, e.g., programmed cell death protein-1(PD-1)/programmed cell death protein-ligand-1 (PD-L1), and identify unknown or little studied CCIs, e.g., the interaction of DCs and B cells. To expand the application of FucoID to complex systems, we also synthesized site-specific antibody-based FT conjugate, which substantially improves the ability of FucoID to probe molecular signatures of specific CCI when cells of interest (bait cells) cannot be purified, e.g., in clinical samples. Collectively, these studies demonstrate the general applicability of FucoID to study unknown CCIs in complex systems at a molecular resolution.

Historically, every thinker's theory on the national political development is topical and pertinent. As time goes by, many scholars have become more and more concerned with the applicability of these ideas to current political situation. This paper will use China and the United States (the U.S.) as examples to analyze the applicability of the theories of Max Weber, Carl Schmitt and Michel Foucault. Based on comparing and summarizing the famous works of the three thinkers, relevant academic papers and reports etc., this article makes a detailed analysis of the applicability of the above thinkers' theories and finally draws conclusions. In terms of Weber, he put forward the idea of distinguishing officials and politicians separately, which is applicable in the U.S. but cannot be applied in China. The main reason for this theory is that officials and politicians are two completely separate systems in the U.S., while China thinks officials is politicians. As for Carl Schmitt, he talks about the distinction between friend and enemy in political relations, and points out the inescapable relationship between politics and war, denying the possibility of peace. This theory perfectly conforms to the current political situation of the U.S., but it has some limitations when it is used to analyze the situation in China due to its unique cultural background as well. For Michel Foucault, the difference between him and the above-mentioned two theorists is that his theory more concerns the people and those in power. However, similar to them, Foucault's theory is also very significant and can be substituted into the modern society of China and the U.S. In conclusion, the theories of Weber, Schmitt, and Foucault are more like a cultural hedge between the old and the new, bringing clear attention to the different political systems in the world.

Objectives: Exosomes are essential mediators of intercellular communication as they transport proteins and RNAs between cells. Owing to their tumor‐targeting capacity, immune compatibility, low toxicity, and long half‐life, mesenchymal stem cell‐derived exosomes have great potential for the development of novel antitumor strategies. In this context, the role of exosomes produced by adipose‐derived mesenchymal stem cells (ADSCs) for the treatment of bladder cancer (BC) remains unclear. Here, we investigated the use of ADSCs as a source of therapeutic exosomes, as well as their efficacy in delivering the tumor suppressor miR‐138‐5p in BC.Methods: ADSCs stably expressing miR‐138‐5p were established using Lentivirus infection, and ADSC‐derived miR‐138‐5p exosomes (Exo‐miR‐138‐5p) were isolated from the cell culture medium. The effect of Exo‐miR‐138‐5p on BC cell migration, invasion, and proliferation was evaluated in vitro using wound healing, transwell invasion, and proliferation assays. The in vivo effect of Exo‐miR‐138‐5p was investigated using a subcutaneous xenograft mouse model.Results: Exo‐miR‐138‐5p prevented the migration, invasion, and proliferation of BC cells in vitro. Moreover, ADSC‐derived exosomes could penetrate tumor tissues and successfully deliver miR‐138‐5p to suppress the growth of xenograft tumors in vivo.Conclusions: The present results reveal that ADSC‐derived exosomes are an effective delivery vehicle for small molecule drugs in vivo, and exosome‐delivered miR‐138‐5p is a promising therapeutic agent for BC treatment.