Overcoming cancer treatment resistance: Unraveling the role of cancer-associated fibroblasts
Xiaoyuan Wang, Yinuo Zhou, Yingzhuo Wang, Jiaxin Yang, Zhengqian Li, F L Liu, Anni Wang, Zhenhao Gao, Chen Wu, Hang Yin
Abstract
CAFs are divided into three main subtypes: myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs). CAFs influence treatment outcomes via seven primary mechanisms: physical barrier formation, metabolic reprogramming, exosome secretion, DNA repair enhancement, bypass signaling activation, activation of multidrug resistance proteins and immune checkpoint inhibition. These mechanisms result in resistance to chemotherapy, radiotherapy, and immune escape, underscoring the critical role of CAFs in the TME and their impact on treatment efficacy. The resistance to cancer treatment is a major clinical obstacle, being strongly influenced by the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are critical elements of the TME. CAFs are heterogeneous and are activated through diverse pathways. These CAFs engage in reciprocal interactions with tumor cells, driving tumor progression and therapeutic resistance. In this review, we discuss the role of CAFs in the development of tumor resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Besides, we summarize recent clinical trials in CAF-targeted therapies. The development of resistance involves physical barrier formation, metabolic reprogramming, exosome release, DNA repair, bypass pathway activation, multidrug resistance protein upregulation, and immune checkpoint inhibition. Challenges remain in addressing drug resistance despite the therapeutic potential of targeting CAFs: the cellular origins of CAFs need to be clarified, and their limited clinical applications need to be increased. Future studies should focus on elucidating the reasons for CAF heterogeneity, developing precise targeting strategies, and validating the clinical safety and efficacy of CAF-based therapies to overcome treatment resistance and improve patient outcomes.