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RECQL4, a RecQ\u2010like helicase, plays a central role in DNA replication and repair as part of the DNA damage response, a pathway implicated in enhancing efficacy of immune checkpoint inhibitor (ICI) therapies. However, its role in patient response to ICI remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analysed whole exome and bulk RNA sequencing data from a pan\u2010cancer cohort of 25\u00a0775 patients and cutaneous melanoma cohorts (untreated: <jats:italic>n<\/jats:italic>\u00a0=\u00a0471, anti\u2010progressive disease [PD]\u20101 treated: <jats:italic>n<\/jats:italic>\u00a0=\u00a0212). <jats:italic>RECQL4<\/jats:italic> copy number variations and expression levels were assessed for patient outcomes. We performed gene set enrichment analysis to identify RECQL4\u2010dependent signalling pathways and explored the association between <jats:italic>RECQL4<\/jats:italic> levels and immunoscores. We evaluated the interplay of ICI response and <jats:italic>RECQL4<\/jats:italic> expression in melanoma cohorts of 95 responders and 85 non\u2010responders prior to and after ICI\u2010targeted therapy and tested the prognostic power of <jats:italic>RECQL4<\/jats:italic>. Finally, we generated genetically engineered RECQL4 variants and conducted comprehensive multi\u2010omic profiling, employing techniques such as liquid chromatography with tandem mass spectrometry, to elucidate mechanistic insights.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified RECQL4 as a critical negative regulator of poor prognosis and response to ICI therapy, but also demonstrated its suitability as an independent biomarker in melanoma. High tumour purity and limited signatures of tumour immunogenicity associated with response to anti\u2010PD\u20101 correlated with high RECQL4 activity. We found alterations in the secretion profile of immune regulatory factors and immune\u2010related pathways robustly suppressed in tumours with high <jats:italic>RECQL4<\/jats:italic> levels, underscoring its crucial role in fostering immune evasion. Mechanistically, we identified RECQL4\u2010mediated regulation of major histocompatibility complex class II molecule expression and uncovered class II major histocompatibility complex transactivator as a mediator bridging this regulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings unraveled the pivotal role of RECQL4 in immune modulation and its potential as both a predictive biomarker and therapeutic target for optimising immunotherapeutic strategies across various cancer types.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>High RECQL4 expression limits survival and can act as an independent prognostic factor in melanoma patients.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>RECQL4 has the potential to act as a negative feedback mediator of immune checkpoint\u2010targeted therapy by limiting signatures associated with therapeutic efficacy.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>RECQL4 favours an immune\u2010evasive phenotype by downregulating major histocompatibility complex class II molecules.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70094","type":"journal-article","created":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T10:03:06Z","timestamp":1736935386000},"source":"Crossref","is-referenced-by-count":2,"title":["RECQL4 affects MHC class II\u2010mediated signalling and favours an immune\u2010evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanoma"],"prefix":"10.1002","volume":"15","author":[{"given":"Sara","family":"Egea\u2010Rodriguez","sequence":"first","affiliation":[{"name":"Department of Dermatology and Allergy University Hospital of Munich Ludwig\u2010Maximilian\u2010University  Munich Germany"},{"name":"German Cancer Consortium (DKTK) Partner Site Munich  Munich 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