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However, intrinsic and acquired resistance in tumor cells significantly limit the clinical efficacy of PTX and are closely associated with treatment failure, tumor recurrence, and poor prognosis. PTX resistance is not driven by a single mechanism but instead arises from the combined effects of multiple regulatory processes, including enhanced drug efflux, microtubule remodeling, evasion of apoptosis, dysregulated autophagic homeostasis, adaptation of the tumor microenvironment (TME), metabolic reprogramming, and aberrant epigenetic regulation. This review systematically summarizes the major molecular mechanisms underlying PTX resistance, with a particular focus on the dynamic interactions among distinct resistance pathways and their regulatory network architecture. It also outlines current resistance-overcoming strategies based on nanodelivery systems, combination therapies, and interventions targeting emerging molecular determinants, as well as the challenges associated with their clinical translation. This review aims to provide a framework for a deeper understanding of the complex biological basis of PTX resistance and to offer insights into the development of more precise therapeutic strategies for overcoming resistance.<\/jats:p>","DOI":"10.3389\/fphar.2026.1909497","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T11:38:24Z","timestamp":1789126704000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Recent advances in research on the multifactorial mechanisms underlying paclitaxel resistance and translational intervention strategies"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhu","family":"Mingjun","sequence":"first","affiliation":[{"name":"Nanjing University of Chinese Medicine","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou","family":"Bingwen","sequence":"additional","affiliation":[{"name":"Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Clinical Innovation Center For Anorectal Diseases","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wang","family":"Lu","sequence":"additional","affiliation":[{"name":"Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Clinical Innovation Center For Anorectal Diseases","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Zhimin","sequence":"additional","affiliation":[{"name":"Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Clinical Innovation Center For Anorectal Diseases","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"109450","DOI":"10.1016\/j.cbi.2021.109450","article-title":"Nuclear factor-\u03baB signaling inhibitors revert multidrug-resistance in breast cancer cells","volume":"340","author":"Abdin","year":"2021","journal-title":"Chem. 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