Targeting inflammation in hepatocellular carcinoma: emerging nanotherapeutic strategies for remodeling immunosuppressive microenvironments

Abstract

Hepatocellular carcinoma (HCC) is one of the most severe malignancies in modern society, and is known as an “inflammatory tumor”, rarely benefiting from immunotherapies. In the inflammatory microenvironment of precancerous HCC, immune cells and stromal cells are transformed from an anti-tumor type into a 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 analyzes the mechanistic links between inflammation-driven immune suppression and progression. We evaluate and categorize cutting-edge nanomedicine approaches designed to initiate immune responses, reverse immunosuppression, and liberate T cell function. Furthermore, we discuss current challenges in clinical translation, particularly those stemming from the physicochemical properties and in vivo behavior of nanocarriers, and proposed strategic directions for next-generation inflammation-targeted nanotherapeutic design, providing new perspectives for breaking the cycle of immune tolerance in HCC.