Melanoma and its fibroblastic allies: the emerging importance of CAFs in immune suppression, ECM modulation, and therapy resistance

Abstract

Melanoma, a heterogeneous and malignant skin tumor, carries disparate prognoses based on the original site of origin, cutaneous, ocular, or mucosal. Advanced and metastatic disease continues to be difficult due to resistance to existing treatments. In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) have multifunctional roles in tumor growth, immune escape, and drug resistance. These heterogeneous stromal cells remodel the extracellular matrix and are angiogenic and immunomodulatory with high concurrence with poor clinical outcomes. It further addresses the role of CAFs in the formation of immunosuppressive niches and BRAF/MEK inhibitor resistance, primarily through mechanisms such as POSTN and β-catenin signaling. Key findings identify CAF-derived exosomes and signaling factors (e.g., TGF-β, IL-6, FGF2, PDPN) as central to melanoma development. Emerging therapy modalities for targeting these stromal elements, such as POSTN inhibition, PEDF restoration, and CAR-T cell treatments, are reviewed. CAFs have long been recognized as pivotal components within melanoma's TME, originating from various sources and manifesting considerable heterogeneity. These cells play an active role in remodeling the extracellular matrix (ECM), stimulating angiogenesis, supporting tumor metabolism, and promoting drug resistance, thereby facilitating tumor growth and metastasis. Through the secretion of various cytokines and growth factors, such as TGF-β and IL-6, they contribute to immune evasion by attracting immunosuppressive cells and impairing the function of cytotoxic T lymphocytes. In this context, we also highlight recent therapeutic strategies aimed at targeting CAFs to enhance treatment efficacy. By examining the diverse functions of CAF subtypes in modulating immune responses and influencing therapeutic outcomes, this review provides deeper insight into CAF-targeted interventions that can disrupt their tumor-supportive roles in melanoma.

Keywords: Cancer-associated fibroblasts; Extracellular matrix; Melanoma; Metastasis; Tumor microenvironment.