Abstract
The cGAS-STING pathway plays a central role in innate immune sensing of cancer and represents a promising target for cancer immunotherapy. We previously demonstrated that nutritional metal ions, such as manganese (Mn(2+)), can potentiate cGAS-STING signaling, amplifying IFN-I responses and driving innate and adaptive anti-tumor immunity. Here, we expand on this concept by developing a controlled-release CDA-Mn(2+) PLGA milli-cylinder implant, designed for a single dose treatment for cancer immunotherapy. Using solvent-extrusion, we formulated poly(D,l-lactide-co-glycolide) (PLGA) 50/50 milli-cylinder implants (I.D. = 0.8 mm) loaded with cyclic di-adenosine monophosphate (CDA) and Mn(2+), achieving high encapsulation efficiency and tunable, sustained release kinetics. In the murine CT26 colon carcinoma model, a single intratumoral injection of the CDA-Mn(2+) PLGA implant induced robust tumor regression and extended animal survival. Mechanistically, the implant reprogrammed the tumor microenvironment and lymphoid tissues, promoted macrophage repolarization, enhanced dendritic cell priming, and significantly increased memory T-cell recruitment. One major limitation of STING-based therapies is the need for frequent intratumoral injections, which hinders patient adherence and increases clinical burden. The CDA-Mn(2+) PLGA implant provides a minimally invasive, patient-centric solution for the sustained co-delivery of multiple small-molecule immune adjuvants, eliminating the need for repeated injections while maintaining therapeutic efficacy. These findings highlight a scalable, cost-effective approach to STING-targeted cancer immunotherapy, with the potential to broaden clinical applications and improve long-term patient outcomes.