Cancer-associated fibroblasts as architects of tumor immune geography and lymphoid organization

Cancer-associated fibroblasts (CAFs) shape how immune cells are organized within tumors and either support or hinder the formation of immune niches associated with clinical outcomes and treatment response known as tertiary lymphoid structures (TLSs). Some CAF states support immune-cell recruitment and TLS establishment, whereas others create dense, fibrotic environments that restrict immune organization. Importantly, the presence of TLSs does not by itself indicate antitumor immunity. Their function depends on surrounding CAFs, extracellular matrix, and blood and lymphatic vessels. In this Review, we argue that the TLS-CAF axis is a key determinant of antitumor immunity, highlighting a potential therapeutic opportunity for selective stromal reprogramming. Cancer-associated fibroblasts (CAFs) are a heterogeneous population of stromal cells that participate in the formation of tertiary lymphoid structures (TLSs). Here, the authors review the current knowledge on how CAF subsets shape the organization and function of immune cells within TLS and discuss the clinical implications of these CAF-TLS interactions.