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While immune checkpoint inhibitors, predominantly PD-1\/PD-L1 blockers, have improved outcomes, resistance and immune-related toxicity remain major challenges. Relatlimab, a lymphocyte activation gene-3 (LAG3) inhibitor, in combination with PD-1 inhibitors, has shown clinical promise, while emerging immune regulators such as\n                    <jats:italic>TIGIT<\/jats:italic>\n                    and\n                    <jats:italic>HAVCR2<\/jats:italic>\n                    are being investigated as potential immunotherapeutic targets. Understanding their roles in SKCM could provide novel therapeutic insights. We investigated the emerging checkpoints LAG3, TIGIT, and HAVCR2 in SKCM using in silico analyses. We analyzed gene expression, immune infiltration, mutational profiles, and methylation patterns using bioinformatic tools, including TIMER, CCLE, Maftools, and UALCAN. Protein expression data were obtained from the Human Protein Atlas, and survival analyses were conducted using Kaplan\u2013Meier plots and Cox regression. Additional molecular and prognostic assessments were performed using MethSurv, Sangerbox, and TISIDB.\n                    <jats:italic>LAG3<\/jats:italic>\n                    ,\n                    <jats:italic>TIGIT<\/jats:italic>\n                    , and\n                    <jats:italic>HAVCR2<\/jats:italic>\n                    were significantly upregulated in SKCM, with higher expression in metastatic compared with primary tumors and associated with improved cumulative survival. Their high expression correlated with increased immune infiltration, particularly by T cells and macrophages, and higher ImmuneScore and StromalScore. Epigenetic regulation through promoter hypermethylation was associated with reduced expression of these genes, suggesting potential immune modulatory mechanisms. Our findings indicate that\n                    <jats:italic>LAG3<\/jats:italic>\n                    ,\n                    <jats:italic>TIGIT<\/jats:italic>\n                    , and\n                    <jats:italic>HAVCR2<\/jats:italic>\n                    may serve as prognostic biomarkers and immunotherapeutic targets in skin melanoma, warranting further investigation. Their roles in immune regulation and tumor progression underscore their relevance in shaping the tumor microenvironment. Future studies should explore their therapeutic potential, particularly in combination with existing immune checkpoint inhibitors, to enhance treatment efficacy. High expression was associated with improved survival; after adjustment for age, AJCC staging, ImmuneScore, and StromalScore, LAG3 and TIGIT showed independent prognostic value, whereas HAVCR2 did not remain significant after FDR correction. Immune-stratified analyses showed that prognostic associations were strongest in immune-high tumors.\n                  <\/jats:p>","DOI":"10.1007\/s10142-026-01832-0","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T05:45:34Z","timestamp":1772084734000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Predicting skin melanoma progression via LAG-3, TIGIT and HAVCR2"],"prefix":"10.1007","volume":"26","author":[{"given":"Paraskevi","family":"Vryza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilias","family":"Georgakopoulos-Soares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4625-5562","authenticated-orcid":false,"given":"Apostolos","family":"Zaravinos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"issue":"8","key":"1832_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2020.100139","volume":"1","author":"V Anagnostou","year":"2020","unstructured":"Anagnostou V, Bruhm DC, Niknafs N et al (2020) Integrative tumor and immune cell multi-omic analyses predict response to immune checkpoint blockade in melanoma. 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This research was conducted using public and de-identified datasets (e.g., TCGA), and thus did not require additional Institutional Review Board (IRB) approval or informed consent. The usage of the TCGA data followed the data usage policies of the National Institutes of Health.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"This research did not receive any specific grant from funding agencies in the public, commercial or non-profit sector.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Financial Support"}},{"value":"During the preparation of this work the authors used ChatGPT to improve the readability and language of the manuscript. After using this tool\/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Generative AI and AI-assisted technologies in the writing process"}},{"value":"not applicable.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Clinical trial number"}},{"value":"The authors declare no competing interests.","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"53"}}