Mechanisms of Paclitaxel Resistance: Recent Advances and Future Perspectives.

Paclitaxel (PTX) is a core first-line chemotherapeutic agent used to treat a broad spectrum of cancers, which remain leading causes of death worldwide. However, the emergence of intrinsic and acquired resistance critically contributes to chemotherapy failure, thereby promoting tumor recurrence and metastasis and resulting in a poor prognosis. PTX resistance is a complex biological process driven by multiple factors and cross-regulated signaling pathways. It encompasses a wide variety of mechanisms, including aberrations in microtubules and related proteins; changes in mitotic systems and chromosomal instability (CIN); epigenetic modifications including ncRNA regulation, DNA methylation, and histone modification; enhanced drug efflux and dysregulation of proliferation and apoptotic signaling pathways; enhanced protective autophagy; metabolic reprogramming; cell plasticity (increased EMT and cancer cell stemness); TME remodeling; and immune regulation. This review systematically examines the core molecular mechanisms of PTX resistance, summarizes cutting-edge strategies to reverse chemoresistance and their clinical translation, and discusses current challenges and future directions, thereby providing a theoretical framework for optimizing PTX-based regimens and overcoming clinical resistance.