Melanoma-associated fibroblasts in tumor-promotion flammation and antitumor immunity: novel mechanisms and potential immunotherapeutic strategies

Abstract

Melanoma, renowned for its aggressive behavior and resistance to conventional treatments, stands as a formidable challenge in the oncology landscape. The dynamic and complex interplay between cancer cells and the tumor microenvironment has gained significant attention, revealing Melanoma-Associated Fibroblasts (MAFs) as central players in disease progression. The heterogeneity of MAFs endows them with a dual role in melanoma. This exhaustive review seeks to not only shed light on the multifaceted roles of MAFs in orchestrating tumor-promoting inflammation but also to explore their involvement in antitumor immunity. By unraveling novel mechanisms underlying MAF functions, this review aims to provide a comprehensive understanding of their impact on melanoma development. Additionally, it delves into the potential of leveraging MAFs for innovative immunotherapeutic strategies, offering new avenues for enhancing treatment outcomes in the challenging realm of melanoma therapeutics.

Keywords: CAF; antitumor immunity; immunotherapy; melanoma-associated fibroblasts; tumor-promotion flammation.

Figure 1

Mechanisms of cancer-associated fibroblasts activation. In addition to inflammatory signals such as IL-1, IL-6, and TNF, stimuli including TGF-β, notch signaling and Eph-ephrins, reactive oxygen species and disrupted metabolism, ECM remodeling, RTK ligands and cytotoxic cancer therapies including chemotheraopy and radiotherapy mediate CAF activation and shape their phenotypes within the TME.

Figure 2

MAFs in tumor-promoting inflammation. MAFs promote tumor progression by inducing the tumor-promoting phenotype of myeloid cells (macrophages and neutrophils) via cyclooxygenase/indoleamine 2,3-dioxygenase-dependent manner, secreting pro-inflammatory cytokines including IL-6, IL-11 and LIF, and suppressing adaptive immune responses involves inhibiting the activity of cytotoxic CD8+ T cells through the recruitment of Tregs and MDSCs, as well as the secretion of cytokines.