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Nature Communications paper on therapeutic melanoma inhibition by local micelle-mediated cyclic nucleotide repression

Cancer immunotherapy represents a significant breakthrough in cancer treatment. However, tumors have numerous mechanisms by which they evade destruction by the immune system. It is therefore necessary to decipher and reverse these mechanisms in order to improve immunotherapies.

The second messenger cyclic adenosine monophosphate (cAMP) is used by all cell types and life forms to regulate metabolic activity and gene expression. As a central player in the cell signaling network, cAMP is involved in the pathogenesis of various diseases. In the immune system, disease-induced or pharmacological sustained elevation of cAMP levels dampen the function of all immune cell types. Regulatory Tcells, unlike other T cells, accumulate increased intracellular amounts of cAMP and require it for the regulation of other immune cells. Excitingly, tumor infiltrating macrophages (TAM) and the melanoma cells have elevated intracellular cAMP levels and these appear to promote metastasis, drug resistance and suppress immune responses against the tumor. 

Since the cAMP is a secondary messenger, which is involvement in virtually all physiological processes, systemic interference with cAMP levels is simply not an option for therapy. By the use of polymer micelles and peritumoral injections the groups of Matthias Barz, Christian Becker and Tobias Bopp showed that effects of the adenylate cyclase (AC) inhibitor (MDL 12330A) can be limited to the tumor microenvironment. The use of amphiphilic block copolymers based on endogenous amino acids, namely polypept(o)ides (polypeptides-block-polypeptoid copolymers), for the formulation of the drug avoided any detectable toxicity at the applied therapeutic doses. Together, they have now shown that polymeric nanoparticles releasing an AC inhibitor locally in tumor tissue can be used to arrest melanoma growth and induce regression of established tumors. Johan et al. Nature Commun. 2021, DOI: 10.1038/s41467-021-26269-w.

This new kind of immune therapy may provide access to new approaches for the therapy of melanoma.

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