The dynamic interplay between melanoma cells and CAFs: Implications drug resistance and immune evasion and possible therapeutics

Melanoma, a malignancy of varying prognoses across primary sites (cutaneous, ocular, and mucosal), typically displays peculiar treatment challenges in metastatic and refractory settings. Cancer-associated fibroblasts (CAFs) have long been recognized as pivotal components within melanoma's tumor microenvironment (TME), originating from various sources and manifesting considerable heterogeneity. These cells actively produce extracellular matrix (ECM), induce angiogenesis, provide metabolic support, contribute to drug resistance, and feed tumor progression and metastasis. Among the many growth factors and cytokines they secrete, including TGF-β and IL-6, they aid in anti-tumor immunity by recruiting immunosuppressive cells and inhibiting cytotoxic T-cell activity, contributing to immune evasion. These dynamic cells sculpt the tumor's niche, allowing cancer cells to survive and proliferate, and their existence is widely correlated with poor prognosis. Taking a cue from the previously established groundwork of how the surroundings heavily influence tumor development, this review attempts to profile the intricate interaction of melanoma cells with the CAFs, the ECM, and signaling molecules. We explore different subtypes of CAFs, their origins, and how they have evolved in their pro-tumorigenic roles in melanoma. Additionally, we review recent advancements in the therapeutic arsenal targeting CAFs to achieve a more effective treatment response. By detailing the specific roles played by different CAFs subtypes in the modulation of immuno-responses and treatment outcomes, this review will further provide insights into the targeted therapy to disrupt CAFs-mediated tumor support in melanoma.