This PACUPod episode analyzes a Phase 1b2, open-label, multicenter trial of intratumoral cavrotolimod, a TLR9 agonist, combined with anti-PD-1 antibodies (pembrolizumab or cemiplimab) in 58 adults with advanced, unresectable, or metastatic skin cancers, including melanoma, Merkel cell carcinoma, and cutaneous squamous cell carcinoma. The study focuses on safety and tolerability, preliminary efficacy (objective response rate, disease control rate, duration of response), and translational immune profiling. Notable findings include a 12% objective response rate with durable responses and evidence of abscopal activity, alongside robust innate and adaptive immune activation in blood and tumor biopsies. The episode discusses the potential to overcome resistance to prior immunotherapy and the implications for future combination strategies and trials.