Abstract
Cancer remains a major global health problem, second only to cardiovascular disease in mortality. Tumor progression is a complex, multistage process influenced by many factors, including the microbiome, which has been identified as an important contributor to cancer development and treatment response.Chemotherapy remains a mainstay of cancer therapy. Metal-based compounds are being explored as alternatives to platinum drugs; among these, gold complexes show promise, targeting cancer cells via DNA damage, mitochondrial dysfunction, inhibition of thioredoxin reductase, and induction of apoptosis. Unlike many conventional chemotherapies, which disrupt the microbiome and can worsen patient outcomes, we hypothesized that gold complexes might preserve microbial balance and reduce side effects.
This thesis examines gold(I) complexes as both direct anticancer agents and modulators of immune-microbiome interactions. Chapter I outlines the relationship between cancer progression, host immunity, and microbial ecology. It reviews evidence on gut and tumor microbiomes and their roles in therapeutic response and resistance.
Chapter II describes the synthesis of three novel gold(I) complexes and evaluates their anticancer activity in vitro and in vivo.
Chapter III examines effects on the tumor immune environment. Using malignant pleural mesothelioma as a model of aggressive, immunologically cold tumors, we show that gold(I) treatment induces immunogenic cell death and cytotoxic responses that may convert refractory tumors into more immunogenic or “hot” phenotypes.
Chapter IV uses multi-omics to assess systemic microbiome changes. It identifies shifts in gut and tumor microbiota, links microbiome remodeling to antitumor effects, and proposes mechanistic explanations.
Chapter V presents a translational research platform that links gut and tumor microbiome signatures to chemotherapy response in esophagogastric adenocarcinoma. The study proposes a mechanistic framework for how longitudinal microbiome dynamics, particularly during platinum-based regimens, influence therapeutic resistance and immune–metabolic adaptation. By combining multi-omics profiling with clinical outcome mapping across geographically stratified cohorts, it addresses gaps at the intersection of microbial ecology and chemotherapy efficacy.
Overall, this work advances a microbiome-focused approach to metal-based anticancer therapy, showing that gold(I) complexes can combine direct cytotoxicity with microbiome-mediated immune effects. By integrating chemical biology, immunology, and microbiomics, the thesis points toward lower-toxicity, more targeted cancer treatments.
| Date of Award | 5 Aug 2025 |
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| Original language | English |
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| Supervisor | Masha BABAK (Supervisor) |