Two active components, derived from dragon's blood, elicit a synergistic antitumor immune response in hepatocellular...

Hepatocellular carcinoma (HCC) remains a serious public health concern worldwide, and conventional therapies exert limited efficacy. In situ vaccination (ISV) activates antitumor immunity by inducing immunogenic cell death (ICD), making it a promising immunotherapy. Unfortunately, in HCC, a scarcity of mature DCs and dysfunctional vasculature collectively restrict ISV efficacy. Dragon's blood, a traditional Chinese medicine, is reported to exert potent antitumor effects. In particular, it contains anti-angiogenic agents (e.g., pterostilbene (PS) and ICD-inducing components (e.g., resveratrol (Res)). Therefore, we hypothesized that its antitumor activity may stem from synergistic stimulation of the antitumor immune response by its active components. However, the associated antitumor mechanisms of dragon's blood in HCC remain largely unknown. In this study, we first systematically screened active components with anti-tumor proliferation and ICD-inducing activities in H22 cells from several major components of dragon's blood in vitro. Res, identified as an ICD-active component, in combination with anti-angiogenic PS, was further evaluated in a murine HCC model to determine its antitumor effects and underlying mechanisms. Res induced ICD in H22 cells, and the combination treatment of Res and PS elicited a potent antitumor immune response in HCC. Further mechanistic research revealed that the synergistic efficacy of the combination therapy was associated with Res-induced ICD and PS-increased tumor hemoperfusion, which substantially promoted DC maturation and CTL infiltration, respectively. Overall, the synergistic stimulation of the antitumor immune response by Res and PS suggests their potential as an ISV-related strategy for HCC.