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Their mechanisms extend beyond direct cytotoxicity to include modulation of tumor metabolism\u2014such as glucose, lipid, and glutamine pathways\u2014and the tumor microenvironment (TME), highlighting their multifaceted role in oncology. However, a systematic synthesis of how natural products concurrently target metabolic reprogramming and immune\u2013stromal components across different clinical phases remains lacking. This review delineates the therapeutic applications of natural products\u2014such as flavonoids, alkaloids, and terpenoids\u2014across the clinical continuum, including perioperative support, concurrent chemoradiotherapy, maintenance therapy, and metastasis suppression. We detail their actions in disrupting core metabolic pathways and elucidate their influence on TME components like cancer\u2010associated fibroblasts, extracellular matrix, and immune cells including tumor\u2010associated macrophages and T lymphocytes. Furthermore, we discuss innovative delivery strategies\u2014including nanocarriers and codelivery systems\u2014that enhance bioavailability and enable synergistic combination with chemotherapy or immunotherapy. By integrating mechanistic insights with clinical translation strategies, this work provides a comprehensive framework for employing natural products in biomarker\u2010driven, precision oncology regimens, supporting their evolving role in multimodal cancer care.<\/jats:p>","DOI":"10.1002\/mco2.70585","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T11:44:49Z","timestamp":1769600689000},"source":"Crossref","is-referenced-by-count":13,"title":["Natural Products in Cancer Prevention and Therapy: Current Challenges and Future Directions"],"prefix":"10.1002","volume":"7","author":[{"given":"Ruimiao","family":"Qian","sequence":"first","affiliation":[{"name":"College of Chinese Materia Medica Tianjin University of Traditional Chinese Medicine  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Ge","sequence":"additional","affiliation":[{"name":"College of Chinese Materia Medica Tianjin University of Traditional 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