Recent advances in research on the multifactorial mechanisms underlying paclitaxel resistance and translational intervention strategies.

Paclitaxel (PTX) is a well-established chemotherapeutic agent that is widely used in clinical practice. It exerts its antitumor activity primarily by stabilizing microtubules and disrupting mitosis, and it is currently used in the treatment of various solid tumors, including ovarian, breast, non-small cell lung, and gastric cancer. 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.