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Project

Normalising tumour pH to bring the STING back in anti-tumour immunity

Stimulator of interferon genes (STING) agonists are a hot topic in immunotherapy. STING activation usually results in a potent modulation of the immune response within the tumour towards a dominant anti-tumour outcome. Despite many positive results we present you two major limitations and we propose a convenient solution. A first concern is related to the practical limitations of cGAMP, the most commonly applied agonist. cGAMP as a cyclic dinucleotide is expensive, has a challenging synthesis, a poor serum stability and requires advanced delivery systems for intracellular transport. Together, this indicates that for the future progression of STING agonist application non-nucleotide agonists should be developed. Secondly, we believe that STING-targeted immunotherapy is applied in suboptimal conditions. lactic acid related acidosis inside the TME has a suppressive and counterproductive effect on the STING induced cytokine production, DC activation and macrophage repolarisation. Starting by investigating the link between STING activation and tumour acidosis, we move further to rescue the immune suppression via pH normalisation with carbonate buffers. For the efficient and safe delivery we propose a hydrogel system that allows for acid-triggered, sustained release of calcium carbonate microparticles that are loaded with STING agonists.

Date:1 Oct 2021 →  Today
Keywords:STING, immunometabolism, controlled release
Disciplines:Particle design and technology, Cancer therapy, Nanochemistry, Biopharmaceutics, Applied immunology