Our phase Ib neoadjuvant trial demonstrated that oncolytic virus (OV) combined with PD-1 blockade achieved a 77.8% pathological response rate and 81.5% 2-year relapse-free survival in patients with acral melanoma. Here, we report the sustained clinical efficacy from an extended 5-year follow-up and characterize the molecular determinants of resistance to inform a biomarker-driven combinatorial strategy. Thirty patients with resectable acral melanoma were enrolled and followed for 5-year survival. Pre- and post-treatment tumor tissues with matched blood samples were analyzed using integrated WES, WTS, TBS, and Olink proteomics. These multi-omic profiles were leveraged to delineate resistance mechanisms in non-responders, which were subsequently validated in murine melanoma models exploring STING agonist-based combination therapy. At a median follow-up of 62.4 months, the 5-year relapse-free and overall survival rates were 70.7% (95% CI, 53.7–93.0%) and 80.0% (95% CI, 66.9–95.7%), respectively. Integrated multi-omics analyses revealed that non-responders, in contrast to responders, exhibited a failure in therapeutic remodeling of the tumor microenvironment. Specifically, non-responders were characterized by baseline innate immune suppression linked to STING pathway downregulation; low baseline STING expression significantly correlated with diminished immune infiltration and inferior clinical outcomes. In murine melanoma models, pharmacological activation of the STING pathway restored innate immune signaling and synergistically augmented the antitumor efficacy of OV plus PD-1 regimen. These data establish the durable long-term clinical benefits of neoadjuvant OV plus PD-1 blockade in acral melanoma. Our findings identify STING dysfunction as a key mediator of therapeutic resistance, providing a rational for integrating STING agonists to optimize the clinical efficacy of this combinatorial approach. Trial registration Retrospectively registered: NCT04197882, 2019-12-13.
Zhao et al. (Mon,) studied this question.