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Background Acquired resistance is a major limitation of targeted inhibitors and immune checkpoint inhibitors (ICi) in cutaneous melanoma. Resistance can develop from drug-tolerant persister cells (DTPs), slow-cycling subpopulations that maintain viability during drug exposure through non-mutational phenotype switching. Previous studies have predicted therapeutic outcomes in melanoma by classifying heterogeneous tumor populations into transcriptional cell states associated with differential response to targeted inhibitors and ICi. The mesenchymal-like cell state elicits an invasive phenotype and is associated with reduced ICi responses. Our laboratory has previously shown that expression of neural crest transcription factor SOX10, which is highly expressed in melanoma, is lost during treatment with targeted inhibitors and is sufficient to induce a slow-cycling state conferring drug tolerance. Here we show that SOX10-deficient cells are associated with a mesenchymal-like phenotype and upregulate production of fibronectin (FN1), an ECM glycoprotein shown to restrict T cell migration within FN1-dense tumor regions. Despite the association between SOX10 loss and drug tolerance, the role of SOX10 deficiency on the tumor immune microenvironment and its contribution to poor ICi outcome are highly unclear.Methods To address this question, 1014 Sox10+ and Sox10 KO tumors were grown in C57BL/6 mice until a target volume of 400 mm3 was reached. Tumors were enzymatically digested into single cell suspensions for flow cytometry analysis of tumor immune populations, or snap frozen in OCT for immunofluorescence analysis of spatial distributions.Results Here, we show that SOX10-deficient cells are positively enriched in the mesenchymal-like gene signature in both human and mouse models of melanoma, and that this enrichment is dependent on the loss of SOX10. Our in vivo data show that 1014 Sox10 KO tumors exhibit delayed growth relative to control (Sox10+) tumors independently of an adaptive immune response. Analysis of tumor-associated immune populations at baseline revealed a dramatic overall reduction in NK cells and increase in Foxp3+ T regulatory (Treg) cells within Sox10 KO tumors compared to control tumors. While CD8+ T cell frequency was unaltered in Sox10 KO tumors, production of granzyme B was significantly reduced compared to intratumoral CD8+ T cells in control tumors, suggesting impaired cytotoxic immune responses.Conclusions Our research aims to understand how SOX10-deficient melanoma alters the composition and function of the tumor immune microenvironment. Additionally, we aim to uncover the potential effect of aberrant FN1 production on ICi response. Our goal is to identify a novel strategy targeting SOX10-deficient melanoma cells to improve ICi response in patients.