Nanoparticle-Mediated Tumor Microenvironment Remodeling Favors the Communication with the Immune Cells for Tumor Killing

Melanoma is one of the most common types of skin cancer with a bad prognosis and limited treatment options in advanced stages. Immunotherapy has changed the landscape of oncology. Cancer cells can activate various mechanisms to suppress immune responses, such as the immunological checkpoint programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1), whose blockage reactivates immune killing of melanoma cells. Moreover, exposure to inhibitory cytokines such as transforming growth factor-beta (TGF-beta) induces T regulatory cell differentiation, which promotes cancer immunosuppression. These advances provided exciting outcomes in the clinical treatment of melanoma, however, there are still limitations, and a combination of several treatments is usually needed. Based on the above, inhibition of the TGF-beta production and the PD-1/PD-L1 checkpoint may be a feasible strategy to increase T cell infiltration and cytotoxicity and thus overcome tumor immune escape. Here, mesoporous silica nanoparticles loaded with a PD-L1 inhibitor (JQ1, a thienotriazolodiazepine and a potent bromodomain family inhibitor) and capped with polyethyleneimine and a small interfering RNA targeting TGF-beta are reported. An efficient PD-L1 downregulation and TGF-beta silencing are achieved using the nanoparticles, along with the promotion of cancer death. This system demonstrates to be a specific and innovative therapeutic approach for the treatment of melanoma.