Fig. 1

The complex role of cancer-associated fibroblasts (CAFs) and fibroblastic reticular cells (FRCs) in regulating anti-cancer immune responses. a CAFs represent a highly heterogeneous population broadly categorized into three main subsets: myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs). These cells originate from diverse sources and exhibit significant plasticity, allowing interconversion between subtypes in response to different stimuli (dashed arrows). CAFs modulate anti-cancer immune responses through various mechanisms: (i) remodeling the extracellular matrix (ECM) to influence immune cell migration within the tumor, (ii) secreting immunomodulatory molecules, and (iii) in the case of apCAFs, by physically interacting with immune cells via antigen presentation through the major histocompatibility complex class II (MHC-II). Notably, CAFs can exert both immunosuppressive and immunostimulatory effects, indicating the presence of distinct subpopulations that drive these opposing functions.³ b In lung cancer, two primary subpopulations of FRCs, perivascular reticular cells (PRCs) and T-zone reticular cells (TRCs), arise from mural and adventitial CCL19-expressing progenitor cells in healthy lung tissue, following distinct differentiation pathways. FRCs play a pivotal role in the formation of specialized lymphoid structures, such as tertiary lymphoid structures (TLSs), located at the tumor periphery, as well as T-cell racks that connect TLSs and extend into the tumor parenchyma. By physically interacting with CD8⁺ T cells, FRCs promote the acquisition of a fully activated effector phenotype, enhancing anti-cancer responses and thereby restraining lung cancer progression.¹ This figure was created using BioRender (www.biorender.com)