Selective reactivation of STING signaling to target Merkel cell carcinoma

Significance The immune-dampened status of Merkel cell carcinoma (MCC) tumors presents a major obstacle to developing effective immunotherapies. We propose that STING silencing may cause the immunologically “cold” MCC tumor microenvironments by blocking cytokine production and, consequently, impeding cytotoxic T cell infiltration, activation, and killing of tumor cells. Our findings indicate that targeted activation of STING S162A/G230I/Q266I by DMXAA could be a viable strategy for bolstering antitumor adaptive immunity in STING-silenced cancers. DMXAA does not stimulate human STING activity. Therefore, when combined with AAV delivery of STING S162A/G230I/Q266I to primary tumors, it may achieve tumor-specific STING activation without concomitant pathology caused by systemic inflammation frequently observed with traditional human STING agonists. This approach could synergize with existing immune-checkpoint therapies to improve MCC treatment.