Mechanisms and Therapeutic Strategies for Minority Cell‐Induced Paclitaxel Resistance and Tumor Progression Mediated by Mechanical Forces

Abstract Chemotherapy remains a prevalent strategy in cancer therapy; however, the emergence of drug resistance poses a considerable challenge to its efficacy. Most drug resistance arises from the accumulation of genetic mutations in a minority of resistant cells. The mechanisms underlying the emergence and progression of cancer resistance from these minority‐resistant cells (MRCs) remain poorly understood. This study employs force‐induced remnant magnetization spectroscopy (FIRMS) alongside various biological investigations to reveal the mechanical pathways for MRCs fostering drug resistance and tumor progression. The findings show that minority Paclitaxel‐resistant cancer cells have enhanced mechanical properties. These cells can transmit high‐intensity forces to surrounding sensitive cells (SCs) through the force transducer, Merlin. This force transmission facilitates the assimilation of surrounding SCs, subsequently strengthening the contraction and adhesion of tumor cells. This process is termed “mechano‐assimilation,” which accelerates the development of drug resistance and tumor progression. Interestingly, disturbances and reductions of mechano‐assimilation within tumors can restore sensitivity to Paclitaxel both in vitro and in vivo. This study provides preliminary evidence highlighting the contribution of MRCs to the development of drug resistance and malignancy, mediated through mechanical interactions. It also establishes a foundation for future research focused on integrating mechanical factors into innovative cancer therapies.