The Combination of R848 with Sorafenib Enhances Antitumor Effects by Reprogramming the Tumor Immune Microenvironment and Facilitating Vascular Normalization in Hepatocellular Carcinoma

Abstract

Novel promising strategies for combination with sorafenib are urgently needed to enhance its clinical benefit and overcome toxicity in hepatocellular carcinoma (HCC). the molecular and immunomodulatory antitumor effects of sorafenib alone and in combination with the new immunotherapeutic agent R848 are presented. Syngeneic HCC mouse model is presented to explore the antitumor effect and safety of three sorafenib doses alone, R848 alone, or their combination in vivo. R848 significantly enhances the sorafenib antitumor activity at a low subclinical dose with no obvious toxic side effects. Furthermore, the combination therapy reprograms the tumor immune microenvironment by increasing antitumor macrophages and neutrophils and preventing immunosuppressive signaling. Combination treatment promotes classical M1 macrophage‐to‐FTH1high M1 macrophage transition. The close interaction between neutrophils/classical M1 macrophages and dendritic cells promotes tumor antigen presentation to T cells, inducing cytotoxic CD8+ T cell‐mediated antitumor immunity. Additionally, low‐dose sorafenib, alone or combined with R848, normalizes the tumor vasculature, generating a positive feedback loop to support the antitumor immune environment. Therefore, the combination therapy reprograms the HCC immune microenvironment and normalizes the vasculature, improving the therapeutic benefit of low‐dose sorafenib and minimizing toxicity, suggesting a promising novel immunotherapy (R848) and targeted therapy (tyrosine kinase inhibitors) combination strategy for HCC treatment.

Immunoactivity of a hybrid membrane biosurface on nanoparticles: enhancing interactions with dendritic cells to augment anti-tumor immune responses

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Anticancer effect of propranolol on diethylnitrosamine‐induced hepatocellular carcinoma rat model

“…Since HCC is diagnosed at advanced stages, it has poor prognosis and a high mortality rate. [1][2][3] HCC is documented for more than 90% of primary liver tumors, mainly due to chronic inflammation. Alcohol abuse, chronic hepatitis viral infections (B and C), and environmental and chemical toxicants are the main leading causes of the national and international spread of HCC.…”

Prdm1 Positively Regulates Liver Group 1 ILCs Cancer Immune Surveillance and Preserves Functional Heterogeneity

“…Research targeting the immune system is showing increasing clinical promise in liver cancer treatment (20). One of our recent studies also found that Toll-like receptor agonists can significantly enhance the anti-tumor effect of Sorafenib by reconstructing the tumor immune microenvironment and reshaping the vascular system (21).…”