Although significant progress has been made in immune checkpoint inhibitor (ICI) treatment of advanced squamous cell carcinoma (SqCC), most patients still experience acquired drug resistance. We used a dendritic cell-based neoantigen vaccine combined with ICIs to treat advanced SqCC in a PD-1 blockade-resistant patient. The follow-up of this patient after 12 months revealed significant tumor regression. We also identified a new ICI-resistant mutation that could become a potential universal neoantigen target for tumor vaccines. Individualized management of advanced SqCC through a combined neoantigen vaccine and ICI administration could yield beneficial clinical outcomes. Vaccines targeting anti-PD-1-resistant mutations might be of particular benefit to a specific group of solid tumor patients.