Extracellular Vesicle‐Based Therapeutic Targeting of β‐Catenin to Modulate Anticancer Immune Responses in Hepatocellular Cancer

Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death worldwide. Although HCC can respond to immune checkpoint inhibitors, such as monoclonal antibodies against programmed death 1 (PD‐1), many patients fail to respond or develop secondary resistance. Activation of Wnt/β‐catenin signaling can contribute to immune evasion. Mutations in β‐catenin are among the most frequent mutations associated with HCC. Thus, our aim was to directly target β‐catenin to enhance the therapeutic response to immune checkpoint inhibition. A synthetic transgenic mouse model of experimental HCC induced by tyrosine‐protein kinase Met/β‐catenin expression and extracellular vesicles (EVs) as a therapeutic delivery agent was used to evaluate the efficacy of directly targeting β‐catenin on the response to anti‐PD‐1. These studies showed that (1) oncogenic β‐catenin could be therapeutically targeted using a biological nanoparticle‐based delivery approach, (2) targeting β‐catenin using small interfering RNA (siRNA) delivered within EVs can reduce tumor growth, and (3) the therapeutic response to anti‐PD‐1 can be enhanced by concomitantly targeting β‐catenin using therapeutic EVs. These preclinical studies establish the efficacy of the use of biological nanoparticles as an endogenous delivery vehicle for therapeutic RNA delivery and support the use of therapeutic strategies targeting tumor‐intrinsic β‐catenin as an adjunct to anti‐PD‐1‐based therapy. Conclusion: Combination therapy with anti‐PD‐1 and β‐catenin siRNA delivered using biological nanoparticles provides an effective strategy for the treatment of HCC. This strategy could be further exploited into targeted approaches for immune potentiation by countering oncogene‐mediated resistance to immunotherapies.