Nanomedicine-based co-delivery of a calcium channel inhibitor and a small molecule targeting CD47 for lung cancer immunotherapy

Pro-tumoral macrophages in lung tumors present a significant challenge in immunotherapy. Here, we introduce a pH-responsive nanomedicine approach for activating anti-tumoral macrophages and dendritic cells. Using a layered double hydroxide nanosheet carrier, we co-deliver a T-type calcium channel inhibitor (TTA-Q6) and a CD47 inhibitor (RRX-001) into lung tumors. In the tumor acidic environment, TTA-Q6 is released, disrupting cancer cell calcium uptake, causing endoplasmic reticulum stress and inducing calreticulin transfer to the cell surface. Surface calreticulin activates macrophages and triggers dendritic cell maturation, promoting effective antigen presentation and therefore activating antitumor T cells. Simultaneously, RRX-001 reduces CD47 protein levels, aiding in preventing immune escape by calreticulin-rich cancer cells. In lung tumor models in male mice, this combined approach shows anti-tumor effects and immunity against tumor re-exposure, highlighting its potential for lung cancer immunotherapy. Lung cancer is characterized by an immunosuppressive microenvironment, limiting responses to immunotherapies. Here the authors report the design of a pH-responsive nanomedicine for the co-delivery of a T-type calcium channel inhibitor and of a small molecule targeting CD47, promoting anti-tumor immune responses in orthotopic lung cancer preclinical models.

Automated summary

The authors report the design of a pH-responsive nanomedicine for the co-delivery of a T-type calcium channel inhibitor and a small molecule targeting CD47, promoting anti-tumor immune responses in orthotopic lung cancer preclinical models.