The Immune Microenvironment in Liver Cancer: From Analysis to Targeting

Despite advancements in early detection and treatment, liver cancer (LC) remains highly recurrent due to its complex immunosuppressive tumor microenvironment (TME), leading to poor prognosis in advanced stages. Nanomedicines (NMs) offer novel therapeutic strategies for reversing the immunosuppressive TME in LC. This review systematically analysed the diverse mechanisms contributing to immunosuppressive TME formation and explored the potential of smart responsive NMs in targeted drug delivery, immune remodeling, and multimodal therapy. The immunosuppressive TME in LC arises from abnormal physiological conditions, extracellular matrix (ECM) deposition, dysfunction of antigen-presenting cells, exhaustion of T cells, infiltration of immunosuppressive cells, metabolic reprogramming, and microbiota influences. Smart NMs can overcome delivery barriers through passive targeting and ligand-directed active targeting to LC cells via receptors, as well as to immunosuppressive cell populations. NMs can respond to endogenous and exogenous stimuli, enabling precise spatiotemporal drug release. This feature enables integration of chemotherapy, immunotherapy, and physical therapies. Additionally, NMs can reprogram the TME by remodeling physiological conditions, inhibiting ECM deposition, regulating metabolism, inducing immunogenic cell death, and modulating microbiota-derived metabolites. Although toxicity and clinical translation still require further optimization, smart NMs offer a paradigm shift for LC therapy through an integrated "targeted delivery-immune reprogramming" strategy.