Hsu Chou-Yi, Saleh Raed Obaid, Mohammed Jaafaru Sani, Mansuri Nasrin, M M Rekha, Kundlas Mayank, Anand Alex, Sahoo Samir, Zwamel Ahmed Hussein, Hulail Hanen Mahmod
Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan.
Department of Medical Laboratories Techniques, College of Health and Medical Techniques, University of Al Maarif, Al Anbar, 31001, Iraq.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Aug 28. doi: 10.1007/s00210-025-04565-2.
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.
黑色素瘤是一种异质性恶性皮肤肿瘤，根据其起源部位（皮肤、眼部或黏膜）的不同，预后差异很大。由于对现有治疗产生耐药性，晚期和转移性疾病仍然难以治疗。在肿瘤微环境（TME）中，癌症相关成纤维细胞（CAFs）在肿瘤生长、免疫逃逸和耐药性方面具有多种功能。这些异质性基质细胞重塑细胞外基质，具有血管生成和免疫调节作用，且与不良临床结果高度相关。它进一步探讨了CAFs在免疫抑制微环境形成和BRAF/MEK抑制剂耐药性中的作用，主要通过POSTN和β-连环蛋白信号传导等机制。关键发现确定CAF衍生的外泌体和信号因子（如TGF-β、IL-6、FGF2、PDPN）是黑色素瘤发展的核心。本文综述了针对这些基质成分的新兴治疗方式，如POSTN抑制、PEDF恢复和CAR-T细胞治疗。长期以来，CAFs一直被认为是黑色素瘤TME中的关键组成部分，它们起源于各种来源，表现出相当大的异质性。这些细胞在重塑细胞外基质（ECM）、刺激血管生成、支持肿瘤代谢和促进耐药性方面发挥积极作用，从而促进肿瘤生长和转移。通过分泌各种细胞因子和生长因子，如TGF-β和IL-6，它们通过吸引免疫抑制细胞和损害细胞毒性T淋巴细胞的功能来促进免疫逃逸。在此背景下，我们还强调了旨在靶向CAFs以提高治疗效果的最新治疗策略。通过研究CAF亚型在调节免疫反应和影响治疗结果方面的不同功能，本综述更深入地了解了针对CAF的干预措施，这些干预措施可以破坏它们在黑色素瘤中对肿瘤的支持作用。
