The bright side of the stroma: the tumor-suppressive roles of cancer-associated fibroblasts

In the past decades, cancer-associated fibroblasts (CAFs) have emerged as central regulators of the tumor microenvironment (TME). CAFs have been implicated in extracellular matrix (ECM) remodeling, cytokine secretion and the establishment of the desmoplastic niche that supports tumor progression. Consequently, for long time, therapeutic strategies have focused on CAF depletion. However, accumulating evidence have demonstrated that indiscriminate targeting of CAFs can accelerate tumor progression, revealing their functional heterogeneity and a previously underappreciated tumor-restraining role. In this review, we examine the evolving paradigm of CAF biology, highlighting emerging tumor-suppressive CAF subtypes and their underlying mechanisms. We discuss how these findings challenge conventional therapeutic strategies and propose, based on this improved CAF stratification, a conceptual shift toward CAF exploitation rather than elimination. Ultimately, harnessing CAF anti-tumoral properties may open new avenues for more effective and context-specific cancer therapies.