LASIP: Light-Activated STING Immunotherapeutic Patch: A Multifunctional Microneedle Platform for Combinatorial Mild Hyperthermia with Immunotherapy in Breast Cancer

Standard of care cancer therapies are ineffective for many patients. While immunotherapies blocking the programmed cell death ligand 1 (PD-L1) have shown some improvement, >60% of patients are resistant to these therapies. Therefore, innovative combination treatments are imperative that will improve response to immunotherapies and prevent relapse with a minimally invasive approach. In this work, we addressed this critical need by designing a new paradigm in therapeutics with LASIP (Light-Activated STING Immunotherapeutic Patch). LASIP is a transformative dissolvable microneedle patch loaded with antiPD-L1 antibodies, liposomal formulation of drugs (ADU-S100) that activate the stimulator of interferon genes (STING) pathway, and liposomal formulation of a biocompatible dye (IR783) that converts near-infrared light to mild hyperthermia (∼43 °C). Our results in mouse models of 4T1 triple negative breast cancer show that LASIP synergizes STING activation with mild hyperthermia to give rise to immunogenic cell death. This reprograms immunologically "cold" tumors to "hot" phenotype, enhancing dendritic cell (DC) maturation and reducing regulatory T cells (T_regs) in tumors that improves response to PD-L1 blockade. LASIP enables regression of primary tumors, induces a potent abscopal effect, and abrogates distant tumors. Further, by assessing metabolic shifts in both primary and distant tumors we identified glucose, lipids, cholesterol, and both oncogenic and immunosupportive amino acids that drive the therapeutic mechanism of LASIP. We show an "immunometabolic" correlation of these key metabolites to markers of DC maturation, T_regs, STING activation, and cytokines. Our findings demonstrate that by integrating three treatment modalities, LASIP elicits both innate and adaptive immune responses and enables metabolic reprogramming in the tumor microenvironment to enable antitumor immunity.