Work

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

Year: 2026

Type: article

Abstract: 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<0.0001 in TGFα/ c-myc and -88.8% p=0.0159 in DEN/CCl 4 induced HCC mice) and increased objective response rate from 0% to 33% (90% confidence interval [CI] 14.6-58.6) in TGFα/c-myc and to 80% (90% CI 39.6-95.8) in DEN/CCl 4 -induced HCC mice). Flow cytometry revealed reduced PD-1 high CD8 + T cells and enhanced expression of activation markers (Ki67, CD44, IFN-γ) in the combination group. RNA-seq of CD45 + cells and whole-tumor transcriptomes indicated decreased immunosuppression and increased vascular permeability in mice receiving the combination therapy. Immunoblot analysis showed enhanced accumulation of αPD-L1 in tumors following iRGD co-administration. Conclusions iRGD co-administration significantly improves therapeutic efficacy of αPD-L1 in HCC mouse models by increasing intratumoral delivery of αPD-L1 and more effective amelioration of the immunosuppressive tumor microenvironment. This non-conjugated, systemic approach holds strong translational potential to enhance ICI responses in patients with HCC. IMPACT AND CLINICAL IMPLICATIONS Immune checkpoint inhibitors (ICIs) show limited efficacy in hepatocellular carcinoma (HCC), to which poor intratumoral drug delivery is likely to contribute. This study demonstrates that intravenous co-administration of the tumor-penetrating peptide iRGD with anti–PD-L1 significantly improves antibody distribution and therapeutic response in preclinical HCC models without increasing toxicity. These findings are highly relevant for clinicians and researchers aiming to enhance ICI effectiveness in solid tumors. Given the clinical evaluation of iRGD, this simple, non-conjugated strategy offers a feasible and rapidly translatable approach to overcome a key limitation of current ICI therapy, thereby improving outcomes for patients with HCC.

Source: JHEP Reports

DOI: 10.1016/j.jhepr.2026.101731