The gut microbiota, acting as a critical extrinsic endocrine organ, is profoundly involved in the pathological evolution and therapeutic response of hormone-dependent malignancies. This review elucidates the core mechanisms governing the microbiota, endocrine, and immune triple-axis. Multi-omic and biochemical evidence demonstrates that microbial metabolic networks, comprising the estrobolome, androbolome, and progestobolome/corticobolome, rely on enzymatic systems such as β-glucuronidases (GUS) and steroid-17,20-desmolases to execute hormone deconjugation and structural modification, thereby modulating systemic steroid exposure. Concurrently, microbe-derived metabolites, such as secondary bile acids and purine derivatives, act as inter-kingdom messengers. These metabolites remodel the tumor immune microenvironment by antagonizing hormone receptors and activating specific signaling axes, such as the Inosine-A2AR pathway. By modulating localized immune cells like effector T cells and myeloid cells, they play a pivotal role in tumor immune evasion. Furthermore, pharmacomicrobiomics reveals a bidirectional regulation between anti-tumor agents and the gut microbiota, where endocrine and immunotherapeutic drugs can induce microbial dysbiosis, while specific gut taxa contribute to primary or acquired resistance by enzymatically inactivating drugs (e.g., reductive inactivation of Enzalutamide) or providing hormonal precursors through bypass pathways. Facing translational challenges, such as real-world microbiome complexity and the colonization resistance of indigenous flora, we propose treating the human body as a unified host–microbe holobiont system. Future research should leverage gnotobiotic models and genetic causal inference to establish functional causality. These efforts will facilitate the development of precision tools, including ubiquitin–proteasome system (UPS) modulators, microbial enzyme inhibitors, and engineered live biotherapeutics. Collectively, these systems biology strategies offer a robust framework for overcoming therapeutic resistance in hormone-dependent malignancies.

Background/Objectives: Carboxylesterase 1 (CES1) is a key enzyme involved in the bioactivation of ester prodrugs. This study aimed to construct a mechanistic, whole-body, physiologically based pharmacokinetic (PBPK) model to simultaneously predict the pharmacokinetics of CES1-activated prodrugs and their metabolites across different age groups. Methods: A comprehensive whole-body prodrug–metabolite PBPK framework was constructed by integrating age-specific physiological parameters. Oseltamivir and enalapril were evaluated across adult, pediatric, and geriatric populations, whereas cilazapril validation was focused on adult and geriatric cohorts based on clinical data availability. The model was developed and validated in adults, and then extrapolated to pediatric and geriatric populations. Model performance was evaluated by comparing predicted and observed pharmacokinetic parameters, specifically the area under the curve (${AUC}_{0-t}$) and maximum plasma concentration ($C_{max}$), with an acceptance criterion of 0.5- to 2.0-fold error. Results: The majority of observed plasma concentrations fell within the 5th–95th percentiles of predicted profiles. Additionally, for most simulations, the ${AUC}_{0-t}$ and $C_{max}$ were within 0.5- to 2-fold of the observed values. Sensitivity analyses revealed that the exposure of their active metabolites was highly related to the plasma unbound fraction, glomerular filtration rate, and hepatic CES1-mediated bioactivation. Conclusions: This whole-body PBPK framework provides a mechanistic basis for predicting CES1-mediated prodrug disposition across age groups. The framework achieved clinical validation across pediatric, adult, and geriatric populations for oseltamivir and enalapril, and provided proof-of-concept support for extending the approach to cilazapril. This platform may serve as a basis for future pharmacokinetic/pharmacodynamic integration and model-informed dose optimization.