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Malignant melanoma is the most lethal form of skin cancer, and its incidence rates are increasing in Europe, America, and Oceania countries. Despite immune checkpoint inhibitors, such as PD-1 inhibitors, have been shown to have significant therapeutic effects on malignant melanoma, many patients are unresponsive to these treatments, even emerged resistance. There is an urgent need to discover novel biomarkers that might distinguish resistant patients from responders. In this study, we used a series of bioinformatics analyses and experimental validation. The GSE65041 was used for differential expression analysis. Kaplan-Meier was used to assess the prognostic value. ESTIMATE, ssGSEA, EPIC, TIMER, quanTiseq and MCPcounter for estimation of immune infiltration in the tumor microenvironment. We eventually identified that CD3ζ was significantly down-regulated in IHC PD-L1(−) melanoma patients. Low level of CD3ζ expression possessed a poor prognosis. CD3ζ low expression population is significantly associated with lower immune infiltration. In vivo experiment, CD3ζ expression was significantly down-regulated in mice melanoma after intradermally injected with B16–F10R cells. Compared to their wildtype counterparts, melanoma resistant mice treated with nivolumab showed significant reductions in tumor volume and weight when adding CD3ζ. In vitro experiment, the addition of CD3ζ increased nivolumab effection on inhibiting B16–F10R cell viability. Our findings indicated that CD3ζ could be a novel predictive biomarker of PD-1 inhibitor resistance in melanoma. [Display omitted] • CD3ζ is a novel biomarker for predict PD-1 inhibitor responsiveness in melanoma. • CD3ζ is one biomarker reflect the diagnosis and prognosis of melanoma. • CD3ζ low expression inhibit antigen processing presentation. • CD3ζ low expression inhibit immunosuppressive signaling pathways. • CD3ζ low expression reflect poorer clinical staging and shorter survival of melanoma. [ABSTRACT FROM AUTHOR]