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.
Cellular senescence is a stress-response program that coordinates cell-autonomous growth arrest and non-cell autonomous remodeling of the tissue environment. Initially defined through its role in aging and tumor suppression, senescence is now recognized as a highly complex program shaped by cell-intrinsic and environmental factors. This complexity places senescence as a broad stress response mechanism operating at the intersection of metabolic dysfunction, chronic inflammation and tissue repair. Given its constant exposure to metabolic, inflammatory and toxic stress alongside its high regenerative demands, the liver is particularly prone to engage senescence as a protective mechanism to maintain tissue integrity. In this context, senescence exerts dual and often opposing effects. This review discusses the multifaceted roles of senescence along the liver disease trajectory, from its early protective functions in tissue repair to its later pathologic contributions to chronic liver disease and tumor progression, underscoring how cell type, stage of senescence program, disease stage and microenvironmental cues shape these divergent outcomes. We highlight the potential of emerging therapeutic interventions that modulate senescence, including pro-senescence, senolytic, senomorphic, and immune-modulating strategies. Advancing our understanding of the multifaceted roles of cellular senescence will be essential to translate this knowledge into therapies that selectively modulate senescent cell states, harnessing their beneficial effects while limiting their detrimental roles in chronic liver disease and cancer.
