Remodeling of Suppressive Melanoma Microenvironments by Particle-Mediated Modulation of the STING/IL-6/PD-L1 Axis Improves Tumor Immunity and Survival

Despite the considerable success of clinically approved immune-based therapies for treating advanced melanoma, a significant fraction of these patients are not responsive due to mechanisms engaged by the tumor to evade the immune system. Here we report the surprising finding that a clinically validated and tunable self-therapeutic ultrasmall silica nanoparticle prolongs survival in a highly resistant melanoma model in combination with IL-6 and PD-L1 inhibition through its activation of the STING/IL-6/PD-L1 axis and reprogramming of the tumor microenvironment (TME) towards a proinflammatory phenotype. Induction of significant cytotoxic and anti-tumor inflammatory responses lead to differential activation of immune cell populations in a model- and CD8-dependent manner via Type I/II interferon pathways after systemic particle injection. Importantly, these immunostimulatory responses accompany significant reductions in cell populations and receptors driving suppressive activities. Mechanistic insights highlight the potential clinical utility of this platform to maximize anti-tumor immunity and efficacy by subverting suppressive components in the TME. Overall design: Experimental samples were treated with or without C' dots. Total RNA was extracted from FFPE sections using the Quick RNA FFPE kit (Zymo Research) and its integrity checked using a 2100 Bioanalyzer with a DV200 reading as 47-61% for all samples before downstream processes such as library preparation and sequencing.