Emerging strategies to target metastasis and therapy resistance in melanoma

Emerging studies propose new approaches to interfere with melanoma progression. In recognition of melanoma awareness month, at Molecular Oncology, we highlight recently published research articles, focusing on novel therapeutic targets driving metastatic spread and outlining different strategies to overcome resistance to BRAF inhibitors and anti-PD-1 treatment in melanoma patients. Melanoma is the most lethal form of skin cancer, with a strong link to ultraviolet (UV) radiation from sun exposure and artificial tanning, along with genetic and phenotypic risk factors such as fair skin, numerous or atypical nevi, and familial predisposition [1, 2]. Originating from melanocytes, the melanin-producing cells derived from neural crest precursor cells, melanoma most commonly arises in the skin, though it can develop in any tissue comprising melanocytes, such as the eyes or intestine [3]. To date, and as highlighted by the European Code Against Cancer (ECAC), the most effective protection remains prevention through UV protection and early detection by skin examination, enabling surgical cure [4]. Once melanoma has developed, its progression occurs as a multistep process, marked by high aggressiveness, intratumoral heterogeneity, and early metastatic spread, presenting a major clinical challenge. Although initially diagnosed as localized melanoma, up to 50% of patients will progress to metastatic disease, significantly reducing overall survival (OS) [5]. Despite the initial success of targeted therapy and immunotherapy, durable responses remain limited due to both primary nonresponse and acquired resistance [6]. Activating BRAF mutations occur in approximately 50% of cutaneous melanomas, most frequently as BRAFV600E, and have led to the development of BRAF inhibitors (BRAFi) that selectively target these alterations [7, 8]. Although showing strong initial efficacy, many patients develop resistance within 6–7 months. Combination therapy with MEK inhibitors extends progression-free survival, yet resistance and relapse still frequently occur [9]. In immunotherapy, 40%–65% of patients exhibit primary resistance, with acquired resistance further limiting long-term benefit. Key mechanisms include impaired antigen presentation, defects in interferon signaling, and the establishment of an immunosuppressive tumor microenvironment [10]. On the occasion of melanoma awareness month, Molecular Oncology highlights recent articles addressing the challenges of early metastatic spread, as well as primary nonresponse and resistance in melanoma, proposing strategies to overcome these barriers (Fig. 1). Due to the high propensity of melanoma to metastasize, understanding its underlying drivers is essential to improve clinical outcomes. In this context, Wronski et al. [11] identified receptor-interacting serine/threonine-protein kinase 4 (RIPK4) as a critical factor in melanoma invasion and metastasis. Initially characterized in keratinocyte differentiation, RIPK4 is increasingly recognized as a context-dependent modulator of signaling cascades across malignancies. The authors observed that the expression of RIPK4 correlated with disease stage, reaching the highest levels in advanced and metastatic melanoma. In vivo xenograft experiments demonstrated that RIPK4 knockout limits lung metastatic lesions, supporting a role in metastatic colonization. Consistently, RNA-seq analyses of RIPK4-knockout cells revealed alterations in pathways linked to cell motility and invasion, together with reduced migration in transwell-based assays and impaired spheroid formation in 3D models. Mechanistically, loss of RIPK4 induced distinct morphological and cytoskeletal changes, including less flattened morphology and increased membrane blebbing, features commonly associated with amoeboid cell migration. Together, these findings suggest that loss of RIPK4 promotes a partial rather than a complete shift toward amoeboid-like features, thereby restricting the metastatic plasticity in the 3D microenvironment and highlighting RIPK4 as a potential target to limit tumor plasticity and metastatic spread. Regarding established therapies, immunotherapy represents a first-line treatment option in melanoma. Here, the PD-L1/PD-1 axis is a central therapeutic target, in which PD-L1 acts as an immune checkpoint ligand suppressing antitumor immunity through engagement of PD-1 on T cells, thereby dampening T-cell activation. By administering monoclonal antibodies such as durvalumab to patients, PD-L1 is inhibited, relieving T-cell suppression and enabling efficient therapy. Despite enhanced clinical outcomes, therapy response is limited in many cases, due to either failed primary response or acquired resistance [10]. In Franken et al. [12], the authors proposed a new regulatory axis modulating PD-L1 in melanoma cells, suggesting a strategy to enhance the effects of immune checkpoint blockade. By performing cell surface proximity labeling followed by mass spectrometry, they identified the transmembrane protein TSPAN4 as a novel interaction partner of PD-L1. Further, they demonstrated that PD-L1 and TSPAN4 colocalize at migrosomes and retraction fibers. Biologically, TSPAN4 knockdown increased PD-L1 surface levels, particularly after interferon treatment, an effect specific to PD-L1 and not to its paralogue PD-L2, or other membrane proteins such as HLA-ABC. Mechanistically, this increase was mediated by enhanced interaction between PD-L1 and CMTM6, redirecting endocytosed PD-L1 to the plasma membrane and reducing lysosomal degradation. Fluorescence recovery after photobleaching (FRAP) experiments further showed increased lateral mobility of PD-L1 upon TSPAN4 knockdown, indicating that TSPAN4 restricts PD-L1 dynamics. Notably, TSPAN4 knockdown enhanced the binding of recombinant PD-1 protein. In addition, coculture experiments of melanoma and Jurkat T cells indicated increased PD-L1 surface expression upon TSPAN4 knockdown, together with enhanced PD-1 engagement on T cells. Blocking this interaction with durvalumab promoted T-cell activation, consistent with alleviation from PD-1-mediated inhibition. Importantly, TSPAN4 expression correlated with poor patient prognosis, supporting clinical relevance. For patients with an activating BRAF mutation, targeted therapy remains the standard of care [13]. In this context, Wang et al. [14] identified the neural crest-associated gene ERRFI1 as a potential therapeutic target in melanoma. They reported upregulated ERRFI1 expression in primary melanoma compared to melanocytic nevi, which is highest in metastatic melanoma and associated with reduced overall survival (OS). Furthermore, ERRFI1 expression positively correlated with phenotype switching previously linked to acquired resistance [15], characterized by upregulation of the receptor tyrosine kinase AXL and downregulation of the master melanocyte-lineage transcription factors SOX10 and MITF. Transcriptomic analyses revealed that ERRFI1 is consistently dysregulated in melanoma and associated with the upregulation of pathways involved in anti-apoptosis, cell proliferation, differentiation, and neural crest development. Wang et al. further demonstrated that siRNA-mediated knockdown of ERRFI1 reversed AXL and SOX10 expression patterns and reduced cell proliferation, as shown by BrdU assays. When combined with the BRAFi vemurafenib, ERRFI1 knockdown decreased cell viability at lower inhibitor concentrations and increased apoptosis, suggesting enhanced sensitivity and supporting a role for ERRFI1 in melanoma tumorigenesis. Importantly, ERRFI1 expression was elevated in BRAFi-resistant cell lines, and its knockdown restored drug sensitivity. Mechanistically, proteomic analysis showed that ERRFI1 depletion downregulated MAPK/ERK and AKT signaling, indicating that ERRFI1 contributes to pathway reactivation in resistant cells. The authors further explored the emerging role of microRNAs in drug resistance and identified miR-200c as a tumor suppressor directly targeting the 3'UTR of ERRFI1. Modulation of the miR-200c-ERRFI1 axis enhances sensitivity to BRAF inhibition, suggesting a promising strategy to improve targeted therapy outcomes in melanoma. An alternate strategy to overcome emerging resistance to BRAF-targeted therapy is proposed by Eller et al. [16], who exploited metabolic adaptation to overcome resistance to the BRAFi dabrafenib in melanoma. Previous work has shown that RAF kinase signaling can suppress mitochondrial reactive oxygen species (ROS) production, thereby preventing cell death, an effect linked to impaired JNK1/2-dependent activation of the mitochondrial pro-oxidant protein p66Shc [17]. In Eller et al., BRAFi resistance was associated with augmented JNK1/2 kinase activity, p66Shc phosphorylation, and elevated ROS production. Resistant cells exhibit mitochondrial damage, accompanied by compensatory increases in respiratory capacity and enhanced antioxidant defenses, allowing survival under high oxidative stress. Importantly, further ROS induction using phenethyl isothiocyanate (PEITC) led to pronounced cell death, indicating that an altered redox balance associated with compromised mitochondria renders resistant cells selectively vulnerable to ROS-inducing therapeutics. In conclusion, the studies of Wronski, Franken, Wang, and Eller et al. highlight that melanoma progression, metastasis, and therapy resistance arise through diverse yet targetable mechanisms, including tumor plasticity, immune evasion, MAPK reactivation, and metabolic rewiring. Collectively, these publications underscore the importance of integrating multiple approaches to inform the development of more effective therapies that limit resistance and metastatic spread, improving long-term patient survival. This highlight article was prepared as part of the EACR-Molecular Oncology Editorial Fellowship funded by the EACR. The author gratefully acknowledges the support of the Molecular Oncology editorial team, the European Association for Cancer Research (EACR), and the Federation of European Biochemical Societies (FEBS). The author would also like to thank Prof. Dr. Martin Eilers for his generous support of this fellowship during the author's PhD studies. The author declares no conflict of interest.