Disrupting the Tumor's Immunosuppressive Shield: Targeting Cancer-Associated Fibroblasts (CAFs) and TGF-β to Enhance Anti-Tumor Immunity

Abstract

Immunosurveillance, the immune system’s mechanism for eliminating tumor cells, plays a critical role in combating malignancies. Tumor cells, however, can modulate the immune system to induce tolerance, thereby evading immune detection. The tumor microenvironment (TME), comprising various cell types, including pericytes, endothelial cells, immune cells, adipocytes, and Cancer-Associated Fibroblasts (CAFs), contributes significantly to immune evasion, tumor growth, and metastasis [1]. CAF, the most abundant stromal cells within the TME, play a pivotal role in interacting with surrounding cells and secreting extracellular matrix (ECM) components that support tumor progression [2]. Initially believed to be passive, research has revealed that CAFs actively remodel ECM, promote angiogenesis, and facilitate cancer cell survival and proliferation through cross-communication with tumor cells [3]. The TME transitions from an anti-tumor state during early tumor development to a pro-tumor state due to cancer cells’ ability to reprogram immune and stromal components. This reprogramming promotes chronic inflammation, ECM remodeling, altered pH, and immune suppression, creating an environment conducive to tumor progression. CAF-derived growth factors and cytokines, such as Transforming Growth Factor-β (TGF-β), Vascular Endothelial Growth Factor (VEGF), Interleukin-6 (IL-6), and C-X-C Motif Chemokine Ligand 12 (CXCL12), further enhance immune evasion by recruiting immunosuppressive cells and promoting angiogenesis [4]. TGF-β, a multifunctional cytokine, regulates numerous processes, including cell growth, differentiation, apoptosis, and ECM synthesis. Dysregulation of TGF-β signaling contributes to excessive proliferation, immune evasion, and metastasis. High TGF-β expression correlates with poor prognosis, increased metastasis, chemotherapy resistance, and reduced survival rates. Consequently, numerous TGF-β signaling inhibitors are under clinical investigation for cancer treatment. Targeting both cancer cells and the TME, particularly CAFs, has emerged as a promising therapeutic approach to overcome tumor progression and immune evasion. ...