Targeting inflammation in hepatocellular carcinoma: Emerging nanotherapeutic strategies for remodeling immunosuppressive microenvironment

Abstract

Hepatocellular carcinoma (HCC) is one of the most severe malignancies in modern society, which is known as an "inflammatory tumor" and rarely benefits from immunotherapies. In the inflammatory microenvironment of precancerous HCC, immune cells and stromal cells are transformed from anti-tumor type into pro-tumor type by stimuli of different inflammatory factors, oxidative stress and key signaling pathways. This evolution fosters a profoundly immunosuppressive niche, culminating in T cell exhaustion and the failure of immune checkpoint inhibitors (ICIs), which are further limited by systemic adverse events and low response rates. Emerging nanotherapeutic strategies, designed to precisely target and remodel the HCC immune landscape, offer a promising avenue to overcome these limitations. This review analyzed the mechanistic links between inflammation-driven immune suppression and HCC progression. And we evaluated and categorized cutting-edge nanomedicine approaches designed to initiate immune responses, reverse immunosuppression, and liberate T cell function. Furthermore, we discussed current challenges in clinical translation and proposed strategic directions for next-generation inflammation-targeted nanotherapeutics design, providing new perspectives for breaking the cycle of immune tolerance in HCC.