Cancer-associated fibroblasts: central players in cancer hallmarks and therapeutic resistance

The tumour microenvironment (TME) is now recognized as pivotal to cancer progression and treatment outcomes, alongside cancer cell-intrinsic factors. Among TME constitute, cancer-associated fibroblasts (CAFs) are abundant and actively shape tumour biology. They are heterogenous population arising from multiple origins, and engage in dynamic crosstalk with cancer cells and immune infiltrates to promote virtually all the hallmarks of cancer. By influencing and reinforcement of cancer hallmark traits, CAFs create a pro-tumorigenic niche that also protects cancer cells from therapy, in this way, conferring resistance to conventional therapy. Consequently, CAFs have emerged as central players linking cancer hallmarks to therapeutic resistance. This review discusses the origins and phenotypic diversity of CAFs, the mechanisms of their communication with tumour and immune cells, and how these interactions enforce hallmark capabilities of cancer that underlie treatment resistance. We also highlight preclinical and clinical evidence for CAF-driven drug resistance and examine current strategies to target CAFs or their effects. A deeper understanding of CAF heterogeneity and function could pave the way for novel combination therapies that dismantle the tumour-CAF alliance and improve patient outcomes.