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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 \u03b2-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\u2013microbe 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\u2013proteasome 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.<\/jats:p>","DOI":"10.3390\/cancers18081218","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T07:29:29Z","timestamp":1776065369000},"page":"1218","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gut Microbiota Metabolic Reprogramming Drives Endocrine and Immune Resistance in Hormone-Dependent Cancers"],"prefix":"10.3390","volume":"18","author":[{"given":"Zhengqin","family":"Zhu","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libin","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China"},{"name":"Department of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7711-0767","authenticated-orcid":false,"given":"Liefeng","family":"Ma","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luo","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China"},{"name":"Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China"},{"name":"Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou 310022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lasagna, A., De Amici, M., Rossi, C., Zuccaro, V., Corbella, M., Petazzoni, G., Comandatore, F., Sacchi, L., Testa, G., and Ferraris, E. 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