“Convex Lens” of DNA damage: A nanomedicine enhances anti-PD-1 immunotherapy as immunogenic cell death inducer for “cold” melanoma

Abstract

Immune checkpoint blockade therapy combined with DNA-damaging therapy can enhance antitumor effects; however, for low-immunogenic melanoma, the efficacy is limited due to impaired antigen presentation and T cell dysfunction. Therefore, we have developed a self-assembled nanodrug (C-GaP) containing an ATR inhibitor, ceralasertib, which can block the DNA damage response, along with the metal ion gallium(Ⅲ), which is capable of inducing DNA replication stress, further exerting a cascading amplification effect on DNA damage. The C-GaP nanodrug exhibits a uniform size distribution and demonstrates outstanding performance in inducing DNA damage, inhibiting proliferation, and promoting apoptosis and immunogenic cell death (ICD) in melanoma cells. Further experiments demonstrate that the C-GaP nanodrug inhibits the phosphorylation of Chk1, enhances the expression of γ-H2AX and cleaved caspase3, and inhibits the PI3K-AKT pathway in vitro. Intriguingly, the C-GaP nanodrug induces dendritic cell activation by triggering ICD in melanoma cells and further induces the activation of helper T cells and cytotoxic T cells, which result in significant antitumor effects in vivo. Moreover, the administration of C-GaP elevates the PD-L1 expression in tumors, while the combination therapy of C-GaP nanodrug and an anti-PD-1 antibody achieves better tumor-suppressive efficacy. Therefore, this designed C-GaP nanomedicine exhibits an antitumor effect as an inducer of ICD.