Cancer-associated fibroblasts and tertiary lymphoid structure orchestrate the spatial architecture of tumor immunity

Tumor immunity is shaped not only by the cellular composition of the tumor microenvironment (TME), but also by how stromal and immune elements are spatially organized within it. Among these regulators, cancer-associated fibroblasts (CAFs) and tertiary lymphoid structures (TLS) have emerged as two major determinants of the spatial niche of anti-tumor immunity. CAFs comprise heterogeneous and plastic stromal populations that can remodel the extracellular matrix, restrict lymphocyte infiltration, sustain chronic inflammation, and promote therapeutic resistance, while selected subsets may also support antigen presentation and lymphoid organization. In contrast, TLS function as ectopic immune hubs that coordinate local T- and B-cell priming, clonal expansion, and B-cell maturation, and are increasingly associated with favorable prognosis and improved responses to immune checkpoint blockade. In this review, we synthesize recent advances from single-cell and spatial multi-omics studies to examine how CAF states and TLS maturation programs arise, interact, and remodel the immune landscape across tumor types. We propose that the balance between CAF-driven stromal restriction and TLS-associated immune organization is a central determinant of immune exclusion versus immune activation. We discuss how this spatial framework may refine tumor classification, improve patient stratification, and guide therapeutic strategies aimed at stromal reprogramming, TLS induction or maturation, and rational combination immunotherapy, while highlighting innate immune-stromal circuits, including IL-33-activated ILC2s, NCR⁺ ILC3s, LTi-like programs, and myeloid organizer cells, as upstream regulators of TLS neogenesis. By integrating CAF biology, TLS dynamics, and spatial context, this review provides a conceptual framework for understanding and targeting the stromal architecture of tumor immunity.