IL-1 signaling in cancer-associated fibroblasts: shaping fibroblast heterogeneity, tumor immunity, and therapeutic resistance.

Abstract

IL-1 signaling is a central regulator of inflammation and immune responses within the tumor microenvironment, with IL-1α and IL-1β acting as key mediators. Tumors exploit IL-1 signaling through complex autocrine and paracrine interactions among malignant cells, immune cells, and cancer-associated fibroblasts (CAFs) to promote growth and progression. CAFs comprise a heterogeneous population of stromal cells with critical roles in extracellular matrix remodeling, angiogenesis, and immune response modulation. Within the broader spectrum of CAFs exhibiting inflammatory and immunomodulatory programs, inflammatory CAFs (iCAFs) represent a distinct and well-characterized polarized fibroblast state. IL-1 is a key driver of iCAF polarization, acting primarily through NF-κB and JAK/STAT3 signaling to promote the secretion of pro-inflammatory cytokines and chemokines. These factors can enhance malignant tumor-cell phenotypes and establish self-reinforcing stromal-immune circuits that foster immunosuppression and treatment resistance. Although IL-1 signaling represents an attractive therapeutic target, the clinical efficacy of IL-1-targeted approaches has been variable. These divergent outcomes may reflect differences in tumor and patient context, treatment timing, and the functional heterogeneity of the CAF compartment, in which distinct CAF states may differentially contribute to tumor-promoting activities and responses to IL-1 inhibition. Here, we discuss the spatiotemporal dynamics of IL-1 signaling across the tumor-immune-CAF axis and evaluate emerging therapeutic strategies targeting IL-1 signaling and pro-tumorigenic CAF states to overcome immunosuppression and treatment resistance in cancer.