Epigenetic reprogramming of tumor cell–intrinsic STING function sculpts antigenicity and T cell recognition of melanoma

Significance Although cancer immunotherapies have shown potential in inducing durable tumor regression in patients with metastatic melanoma, their efficacy remains highly variable and patient specific. Here, we present one strategy to overcome resistance to T cell–based immunotherapies by pharmacologically modulating the STING pathway, a relatively common suppressed DNA-sensing pathway in human melanomas. We show that rescue of this pathway in human melanoma cells using a clinically available DNA methylation inhibitor can augment their antigenicity and recognition by tumor-infiltrating lymphocytes. These findings have important clinical implications for the development of optimal therapeutic protocols that consider the status of tumor-intrinsic STING activity and provide a strategy to design clinical interventions using T cell–based immunotherapies with appropriate patient selection in melanoma.