Immunogenic Cell Death-Associated miRNAs in the Tumor Microenvironment of Hepatocellular Carcinoma.

Abstract

Hepatocellular carcinoma (HCC) poses significant therapeutic challenges due to its high heterogeneity and immunosuppressive tumor microenvironment (TME). Immunogenic cell death (ICD) represents a promising strategy in cancer therapy by eliciting antitumor immune responses through the controlled release of damage-associated molecular patterns (DAMPs). However, its therapeutic efficacy remains substantially limited by the immunosuppressive TME and the lack of selective targeting of conventional ICD-inducing agents. MicroRNAs (miRNAs) regulate immune checkpoints (e.g., PD-L1), TME populations (e.g., tumor-associated macrophages and regulatory T cells), and DAMPs-related pathways, positioning them to both enhance ICD and relieve its constraints. Clinical translation, however, is hindered by delivery and off-target effects. Emerging nanotechnologies, including pH-responsive and photoresponsive carriers, enable spatiotemporal co-delivery of ICD inducers (e.g., oxaliplatin) and miRNA modulators (e.g., anti-miR-21), thereby augmenting DAMP release, reprogramming the TME, and targeting competing endogenous RNA networks (e.g., lncRNA H19) to overcoming resistance. In this Review, with a focus on clinical translation, we argue that combining ICD, immune checkpoint blockade, and miRNA modulation offers a coherent framework to turn cold HCC tumors into responsive ones, thereby increasing treatment precision and sustaining benefit.