Co-administered internalizing RGD peptide boosts anti-PD-L1 therapy in hepatocellular carcinoma

Background & Aims Immune checkpoint inhibitor (ICI) therapy has significantly improved the treatment of solid tumors such as hepatocellular carcinoma (HCC), yet most patients fail to respond. Here, we examined whether co-administration of the tumor-penetrating internalizing (i)RGD peptide that selectively increases tumor vascular permeability in a neuropilin-1-dependent manner, enhances intratumoral delivery and therapeutic efficacy of αPD-L1 in mouse models of HCC. Methods αPD-L1 with or without iRGD was administered intravenously in mice bearing endogenous HCCs (TGFα/c-myc and DEN/CCl 4 models). Tumor growth was monitored by magnetic resonance imaging. Immune cell composition and activation were analyzed by flow cytometry. RNA sequencing was performed on both whole tumors and isolated intratumoral CD45 + immune cells. Results While αPD-L1 monotherapy had minimal impact on tumor progression, combination treatment with iRGD significantly improved therapeutic efficacy, resulting in markedly reduced tumor growth (mean difference -198.2% p