Treg-derived exosomal miR-146a orchestrates bidirectional Treg-CAF crosstalk to sustain immunosuppressive tumor microenvironments.

Resistance to immunotherapy is often reinforced by the resilient immunosuppressive architecture of the tumor microenvironment (TME). Although the crosstalk between regulatory T cells (Tregs) and cancer-associated fibroblasts (CAFs) is increasingly recognized as an important contributor to this resistance, the specific molecular links that sustain this interaction remain incompletely understood. This review proposes a bidirectional Treg-derived exosomal miR-146a-CAF signaling model to explain how immunosuppressive remodeling may be maintained. Current evidence suggests that activated Tregs can release exosomes enriched in miR-146a and may thereby influence the response state of recipient CAFs through signaling nodes such as TRAF6/IRAK1, NF-κB, and JAK2-STAT3. Meanwhile, CAF-derived signals may support Treg recruitment and functional maintenance. Through the secretion of chemokines and cytokines such as CCL2, CXCL12, TGF-β, and IL-6, CAFs contribute to Treg recruitment, local persistence, and suppressive function. Because these processes are currently supported largely by indirect evidence derived from different experimental models, this review integrates them into a bidirectional Treg-CAF communication framework that requires further validation, rather than presenting them as a fully established causal feedback loop. To therapeutically interrogate and potentially disrupt this putative circuit, we discuss strategies focused on blocking exosome biogenesis, neutralizing extracellular miR-146a, or disrupting downstream metabolic and signaling dependencies. These strategies are better viewed as candidate approaches for validating and intervening in this model, rather than as clinically mature targeted therapies. By distinguishing validated mechanisms from indirect evidence and testable inferences, this review aims to provide a clearer experimental framework and potential translational directions for future studies.